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There has been strong interest in the role of metals in neurodegeneration, and how ageing may predispose the brain to related diseases such as Alzheimer's disease. Recent work has also highlighted a potential interaction between different metal species and various components of the cytoskeletal network in the brain, which themselves have a reported role in age-related degenerative disease and other neurological disorders. Neurofilaments are one such class of intermediate filament protein that have a demonstrated capacity to bind and utilise cation species. In this study, we investigated the consequences of altering the neurofilamentous network on metal ion homeostasis by examining neurofilament light (NFL) gene knockout mice, relative to wildtype control animals, at adulthood (5 months of age) and advanced age (22 months). Inductively coupled plasma mass spectroscopy demonstrated that the concentrations of iron (Fe), copper (Cu) and zinc (Zn) varied across brain regions and peripheral nerve samples. Zn and Fe showed statistically significant interactions between genotype and age, as well as between genotype and region, and Cu demonstrated a genotype and region interaction. The most substantial difference between genotypes was found in Fe in the older animals, where, across many regions examined, there was elevated Fe in the NFL knockout mice. This data indicates a potential relationship between the neurofilamentous cytoskeleton and the processing and/or storage of Fe through ageing. [ABSTRACT FROM AUTHOR]

The serendipitous discovery of triggered autobiographical memories and eventual memory improvement in an obese patient who received fornix deep brain stimulation in 2008 paved the way for several phase I and phase II clinical trials focused on the safety and efficacy of this potential intervention for people with Alzheimer's disease. In this article, we summarize clinical trials and case reports on fornix deep brain stimulation for Alzheimer's disease and review experiments on animal models evaluating the physiological or behavioral effects of this intervention. Based on information from these reports and studies, we identify potential translational challenges of this approach and determine practical and ethical considerations for clinical trials, focusing on issues regarding selection criteria, trial design, and outcome evaluation. Based on initial results suggesting greater benefit for those with milder disease stage, we find it essential that participant expectations are carefully managed to avoid treatment disenchantment and/or frustration from participants and caregivers. Finally, we urge for collaboration between centers to establish proper clinical standards and to promote better trial results comparison. [ABSTRACT FROM AUTHOR]

There is increasing evidence that epigenetic alterations may play a role in Alzheimer's disease (AD); yet, there is little information regarding epigenetic modifications in specific cell types. We assessed DNA methylation (5-methylcytosine [5mC]) and hydroxymethylation (5-hydroxymethylcytosine [5hmC]) marks specifically in neuronal and glial cell types in the inferior temporal gyrus of human AD cases and age-matched controls. Interestingly, neurofilament (NF)–labeled pyramidal neurons that are vulnerable to AD pathology are deficient in extranuclear 5mC in AD cases compared with controls. We also found that fewer astrocytes exhibited nuclear 5mC and 5hmC marks in AD cases compared with controls. However, there were no alterations in 5mC and 5hmC in disease-resistant calretinin interneurons or microglia in AD, and there was no alteration in the density of 5mC- or 5hmC-labeled nuclei in near-plaque versus plaque-free regions in late-AD cases. 5mC and 5hmC were present in a high proportion of neurofibrillary tangles, suggesting no loss of DNA methylation marks in tangle bearing neurons. We provide evidence that epigenetic dysregulation may be occurring in astrocytes and NF-positive pyramidal neurons in AD. [ABSTRACT FROM AUTHOR]

Abstract: There has been growing interest in the axon as the initial focus of pathological change in a number of neurodegenerative diseases of the central nervous system. This review concentrates on three major neurodegenerative conditions – amyotrophic lateral sclerosis, multiple sclerosis and Alzheimer''s disease – with emphasis on key cellular changes that may underlie early axonal dysfunction and pathology and, potentially, the degeneration of neurons. In particular, this review will address recent data that indicate that the main pathological stimuli for these conditions, though often not definitively determined, result in an initial perturbation of the axon and its cytoskeleton, which then results in slow neuronal degeneration and loss of connectivity. The identification of a degenerative process initiated in the axon may provide new therapeutic targets for early intervention to inhibit the grim outcomes related to the progression of these diseases. [Copyright &y& Elsevier]

Abstract: The morphology and neurochemistry of β-amyloid (Aβ) plaque-associated dystrophic neurites present in TgCRND8 and Tg2576 mice was demonstrated to be strikingly similar to that observed in pathologically aged human cases, but not in Alzheimer''s disease (AD) cases. Specifically, pathologically aged cases and both transgenic mouse lines exhibited α-internexin- and neurofilament-triplet-labelled ring- and bulb-like dystrophic neurites, but no classical hyperphosphorylated-tau dystrophic neurite pathology. In contrast, AD cases demonstrated abundant classical hyperphosphorylated-tau-labelled dystrophic neurites, but no neurofilament-triplet-labelled ring-like dystrophic neurites. Importantly, quantitation demonstrated that the Aβ plaques in TgCRND8 mice were highly axonopathic, and localised displacement or clipping of apical dendrite segments was also associated with Aβ plaques in both transgenic mouse models. These results suggest that neuronal pathology in these mice represent an accurate and valuable model for understanding, and developing treatments for, the early brain changes of AD. [Copyright &y& Elsevier]

Cytochrome c has a well-established role in electron transfer and as a mediator of apoptotic cell death. The cortical and intracellular localisation of cytochrome c immunoreactivity was examined in Alzheimer's disease and control cases. No differences in the cortical labelling pattern or the density of cytochrome c-positive cells in neocortical layer V were present between control and Alzheimer's disease cases. Punctate cytochrome c labelling was present in a subset of neocortical neurons, including clusters of intensely labelled pyramidal neurons that were not specifically associated with β-amyloid plaques. With respect to Alzheimer's disease associated pathology, only 6.7 ± 1.4% of neurons showing neurofibrillary tangle formation demonstrated punctate cytochrome c immunoreactivity. These results suggest that cytochrome c may label a subset of pyramidal neurons that is susceptible, yet relatively resistant, to Alzheimer's disease pathology. A low percentage of neurofilament triplet protein medium, tau and chromogranin A labelled dystrophic neurites were also cytochrome c-positive. There was also a trend towards an increase in the percentage of cytochrome c immunoreactive dystrophic neurites in pathologically aged control cases compared to Alzheimer's disease cases, suggesting that cytochrome c may be an early and transient epitope within dystrophic neurites. In contrast to the punctate cytochrome c labelling observed in cortical cells, cytoplasmic cytochrome c labelling was observed within dystrophic neurites. Although cytochrome c release is indicative of the activation of the intrinsic apoptotic pathway, cytoplasmic cytochrome c may also indicate mitochondrial damage or dysfunction. [ABSTRACT FROM AUTHOR]

Regeneration of the adult central nervous system may require recapitulation of developmental events and therefore involve the re-expression of developmentally significant proteins. We have investigated whether the L1 cell adhesion molecule, and its binding partner, the ezrin-radixin-moesin (ERM) proteins are involved in the neuronal regenerative response to injury. Hippocampal and cortical neurons were culturedin vitroon either an L1 substrate or poly-L-lysine, and ERM and other neuronal proteins were localized immunocytochemically both developmentally and following neurite transection of neurons maintained in long-term culture. Activated ERM was localized to growth cones up to 7 daysin vitrobut relatively mature cultures (21 daysin vitro) were devoid of active ERM proteins. However, ERM proteins were localized to the growth cones of sprouting neuronal processes that formed several hours after neurite transection. In addition, the L1 substrate, relative to poly-L-lysine, resulted in significantly longer regenerative neurites, as well as larger growth cones with more filopodia. Furthermore, neurons derived from the cortex formed significantly longer post-injury neurite sprouts at 6 h post-injury than hippocampal derived neurons grown on both substrates. We have demonstrated that L1 and the ERM proteins are involved in the neuronal response to injury, and that neurons derived from the hippocampus and cortex may have different post-injury regenerative neurite sprouting abilities. [ABSTRACT FROM AUTHOR]

Presents a study which examined the cytoskeletal dynamics that characterize neurite sprouting after axonal injury to cortical neurons maintained in culture for several weeks and compared these with initial neurite development. Materials and methods; Results; Discussion and findings.

Investigates the effect of metallothioneins (MT) isoforms, MT-IIA and MT-III, on neurite sprouting and growth. Effect of MT-IIA on the neuronal response to injury; Benefits from exogenous application of MT-IIA after cortical brain injury; Information on the opposing neuroactive properties of the MT isoforms.

Summary: Isolated rapid eye movement (REM) sleep behaviour disorder (iRBD) is a sleep disorder that is characterised by dream enactment episodes during REM sleep. It is the strongest known predictor of α‐synuclein‐related neurodegenerative disease (αNDD), such that >80% of people with iRBD will eventually develop Parkinson's disease, dementia with Lewy bodies, or multiple system atrophy in later life. More research is needed to understand the trajectory of phenoconversion to each αNDD. Only five 'gold standard' prevalence studies of iRBD in older adults have been undertaken previously, with estimates ranging from 0.74% to 2.01%. The diagnostic recommendations for video‐polysomnography (vPSG) to confirm iRBD makes prevalence studies challenging, as vPSG is often unavailable to large cohorts. In Australia, there have been no iRBD prevalence studies, and little is known about the cognitive and motor profiles of Australian people with iRBD. The Island Study Linking Ageing and Neurodegenerative Disease (ISLAND) Sleep Study will investigate the prevalence of iRBD in Tasmania, an island state of Australia, using validated questionnaires and home‐based vPSG. It will also explore several cognitive, motor, olfactory, autonomic, visual, tactile, and sleep profiles in people with iRBD to better understand which characteristics influence the progression of iRBD to αNDD. This paper details the ISLAND Sleep Study protocol and presents preliminary baseline results. [ABSTRACT FROM AUTHOR]

Brain-derived neurotropic factor (BDNF) is an abundant and multi-function neurotrophin in the brain. It is released following neuronal activity and is believed to be particularly important in strengthening neural networks. A common variation in the BDNF gene, a valine to methionine substitution at codon 66 (Val66Met), has been linked to differential expression of BDNF associated with experience-dependent plasticity. The Met allele has been associated with reduced production of BDNF following neuronal stimulation, which suggests a potential role of this variation with respect to how the nervous system may respond to challenges, such as brain ageing and related neurodegenerative conditions (e.g., dementia and Alzheimer's disease). The current review examines the potential of the BDNF Val66Met variation to modulate an individual's susceptibility and trajectory through cognitive changes associated with ageing and dementia. On balance, research to date indicates that the BDNF Met allele at this codon is potentially associated with a detrimental influence on the level of cognitive functioning in older adults and may also impart increased risk of progression to dementia. Furthermore, recent studies also show that this genetic variation may modulate an individual's response to interventions targeted at building cognitive resilience to conditions that cause dementia. [ABSTRACT FROM AUTHOR]

We investigated the cellular localisation of neurofibrillary tangles in Alzheimer’s disease. All tau-positive tangles were stained for thioflavine S, while ∼84% of thioflavine S-stained tangles were tau-immunolabelled. Approximately 58–62% and 73–76% of thioflavine S- and tau-labelled tangles, respectively, were present within cortical neurons labelled for microtubule-associated protein-2. Thus, most neocortical tangles in Alzheimer’s disease are intracellular and may not be the principal cause of neocortical cell loss. [Copyright &y& Elsevier]

Issue Addressed: Gender and bilingualism are reported to influence the risk of dementia. This study examined the prevalence of self‐reported modifiable dementia risk factors by gender in two samples: one that speaks at least one language other than English (LoE) and one that speaks only English. Methods: A descriptive cross‐sectional study was conducted on a sample of Australian residents aged 50 years or over (n = 4339). Participant characteristics and dementia risk behaviours were inspected using descriptive statistics in data collected via online surveys between October 2020 and November 2021. Results: In both samples, men had a higher rate than women of being overweight and were classified more frequently as being at risk of dementia due to alcohol consumption, lower cognitive activity, and non‐adherence to the Mediterranean‐style diet. Men reported better management of their cardiometabolic health than women across both groups. Non‐significant trends showed men were more often smokers but more physically active than women in the LoE group, and less often smokers but less physically active than women in the English‐only group. Conclusion: This study found men and women reported similar patterns of dementia risk behaviours regardless of LoE or English‐only status. So What?: Gender differences in risk behaviours prevail regardless of language‐speaking status. The results can be used to guide future research aiming to understand and reduce modifiable dementia risk in Australia and beyond. [ABSTRACT FROM AUTHOR]

Background: Unmanaged cardiometabolic health, low physical and cognitive activity, poor diet, obesity, smoking and excessive alcohol consumption are modifiable health risk factors for dementia and public health approaches to dementia prevention have been called for. The Island Study Linking Ageing and Neurodegenerative Disease (ISLAND) is a dementia prevention public health study examining whether improving knowledge about modifiable dementia risk factors supports behaviour changes that reduce future dementia risk. Methods: Residents of Tasmania, Australia, aged 50 + years who joined the 10-year ISLAND study were asked to complete annual online surveys about their knowledge, motivations and behaviours related to modifiable dementia risk. ISLAND included two knowledge-based interventions: a personalised Dementia Risk Profile (DRP) report based on survey responses, and the option to do a 4-week Preventing Dementia Massive Open Online Course (PDMOOC). Longitudinal regression models assessed changes in the number and type of risk factors, with effects moderated by exposures to the DRP report and engagement with the PDMOOC. Knowledge and motivational factors related to dementia risk were examined as mediators of risk behaviour change. Results: Data collected between October 2019 and October 2022 (n = 3038, av. 63.7 years, 71.6% female) showed the mean number of modifiable dementia risk factors per participant (range 0 to 9) reduced from 2.17 (SD 1.24) to 1.66 (SD 1.11). This change was associated with the number of exposures to the DRP report (p =.042) and was stronger for PDMOOC participants (p =.001). The interaction between DRP and PDMOOC exposures yielded a significant improvement in risk scores (p =.004). The effect of PDMOOC engagement on behaviour change was partly mediated by increased knowledge (12%, p =.013). Self-efficacy enhanced the effect of knowledge on behaviour change, while perceived susceptibility to dementia mitigated this relationship. Conclusions: The ISLAND framework and interventions, a personalised DRP report and the four-week PDMOOC, work independently and synergistically to increase dementia risk knowledge and stimulate health behaviour change for dementia risk reduction. ISLAND offers a feasible and scalable public health approach for redressing the rising prevalence of dementia. [ABSTRACT FROM AUTHOR]

Objectives: Unequal access to cognitive assessments is a major barrier to timely diagnosis, especially for those living in rural or remote areas. 'One‐stop' cognitive clinic models are a proposed solution, but few such clinics exist. We evaluate the implementation of a new one‐stop State‐wide clinic model in Tasmania, Australia, where 27% of people live in rural/remote areas. Methods: A novel single‐visit protocol has been developed, comprising interdisciplinary medical and cognitive assessments, research participation, consensus diagnosis and management plan. A cross‐sectional evaluation was undertaken using the RE‐AIM (reach, effectiveness, adoption, implementation, maintenance) framework and results benchmarked against the national Australian Dementia Network Registry. Results: Over the first 52 consecutive weekly clinics: Reach: 130 adults were assessed (mean age [SD] 70.12 years [10.31]; 59.2% female) with 40 (36.8%) from rural/remote areas. Effectiveness: 98.5% (128/130) received a same‐day diagnosis: 30.1% (n = 40) Subjective Cognitive Decline, 35.4% (46) Mild Cognitive Impairment, 33.1% (43) dementia and one case inconclusive. Adoption: 22.9% (156) of General Practitioners referred patients. Implementation: Nearly all 'ideal' diagnostic clinical practices were met and >90% of surveyed patients reported 'good/very good' clinic experience. The wait from referral to diagnosis was 2 months shorter than other national Registry clinics (78 vs. 133 days). Conclusions: This 'one‐stop' model provides an interdisciplinary consensus cognitive diagnosis quickly and is well accepted; this may reduce health inequities especially for people living in rural/remote areas. This cognitive clinic model may be of relevance to other centres worldwide and also provides a rich data source for research studies. Key points: Access to cognitive assessments is unequal, especially for people living in rural areas.A 'one‐stop' cognitive clinic resulted in 98.5% same‐day diagnosis, 2 months earlier than the national averageOne‐third of people assessed were from rural/remote areas.This model may inform service design for centres worldwide and provides rich data for research. [ABSTRACT FROM AUTHOR]

While the prevalence of non-communicable disease risk factors is understood to be higher among migrants than for people born in host nations, little is known about the dementia risk profile of migrants, refugees and asylum seekers. This systematic review examines published literature to understand what is currently reported about 12 identified modifiable risk factors for dementia among migrants, refugees, and asylum seekers residing in Australia. Three literature databases (PubMed/CINAHL/MEDLINE) were systematically searched to find articles reporting excessive alcohol consumption, traumatic brain injury, air pollution, lack of education, hypertension, hearing impairment, smoking, obesity, depression, physical inactivity, diabetes, and limited social contact in Australia's migrant, refugee and asylum seeker population samples. Papers were systematically reviewed following PRISMA guidelines. A total of 763 studies were found, of which 676 articles were excluded, and 79 articles remained. Despite wide variability in study design, size and purpose, the prevalence and correlates of modifiable risk factors of dementia appears markedly different among the studied samples. Compared with Australian-born participants, migrant samples had a higher prevalence of depression, social isolation, physical inactivity and diabetes mellitus. Insufficient information or conflicting evidence prevented inference about prevalence and correlates for the remaining dementia risk factors. A better understanding of the prevalence and correlates of modifiable dementia risk factors is needed in Australia's migrant, refugee and asylum seeker populations. This information, together with a deeper understanding of the contextual and cultural contributing factors affecting people who arrive in Australia through differing pathways is needed before preventive interventions can be realistically targeted and sensitively implemented. [ABSTRACT FROM AUTHOR]

Introduction: There is evidence that the e4 allele of the apolipoprotein E (APOE) gene is detrimental to cognitive function, but results from traumatic brain injury (TBI) populations are mixed. A possible explanation is that APOEe2 carriers have routinely been incorporated into APOEe4 and non-e4 groups, despite APOEe2 being proposed to have an ameliorative effect. Our primary aim was to investigate the influence of APOEe4 on cognitive impairment during early recovery following TBI, excluding the potential confound of APOEe2 possession. A secondary objective was to explore whether APOEe4 displays more pronounced effects in moderate to severe TBI and to consider the potential postinjury protective influence of the APOEe2 allele.Method: Participants who recently sustained a TBI (posttraumatic amnesia > 5 minutes) were assessed on measures of information processing speed, executive function, and working memory upon remission of posttraumatic amnesia. APOE genotype was determined by buccal saliva DNA extraction (APOEe4n= 37, APOEe3n= 92, APOEe2n= 13).Results: Stepwise multiple regressions were performed to compare APOEe4 carriers to APOEe3 homozygotes, with injury severity, age, and estimated premorbid IQ included in the first step. This model was found to significantly predict performance on all tasks, accounting for 17.3–24.3% of the variance. When APOEe4 status was added for the second step, there were no significant changes on any tasks (additional variance <1%). The effect of APOEe4 in moderate to severe TBI and the effect of APOEe2 were explored by analysis of covariance (ANCOVA), with no significant effects revealed.Conclusions: It is unlikely that APOE genotype influences cognitive function in the initial recovery period following TBI, regardless of injury severity. However, a more nuanced and long-term exploration of the effect of APOE genotype in the TBI population is warranted. [ABSTRACT FROM AUTHOR]

Background: The worldwide prevalence of dementia is rapidly rising. Alzheimer's disease (AD), accounts for 70% of cases and has a 10-20-year preclinical period, when brain pathology covertly progresses before cognitive symptoms appear. The 2020 Lancet Commission estimates that 40% of dementia cases could be prevented by modifying lifestyle/medical risk factors. To optimise dementia prevention effectiveness, there is urgent need to identify individuals with preclinical AD for targeted risk reduction. Current preclinical AD tests are too invasive, specialist or costly for population-level assessments. We have developed a new online test, TAS Test, that assesses a range of motor-cognitive functions and has capacity to be delivered at significant scale. TAS Test combines two innovations: using hand movement analysis to detect preclinical AD, and computer-human interface technologies to enable robust 'self-testing' data collection. The aims are to validate TAS Test to [1] identify preclinical AD, and [2] predict risk of cognitive decline and AD dementia.Methods: Aim 1 will be addressed through a cross-sectional study of 500 cognitively healthy older adults, who will complete TAS Test items comprising measures of motor control, processing speed, attention, visuospatial ability, memory and language. TAS Test measures will be compared to a blood-based AD biomarker, phosphorylated tau 181 (p-tau181). Aim 2 will be addressed through a 5-year prospective cohort study of 10,000 older adults. Participants will complete TAS Test annually and subtests of the Cambridge Neuropsychological Test Battery (CANTAB) biennially. 300 participants will undergo in-person clinical assessments. We will use machine learning of motor-cognitive performance on TAS Test to develop an algorithm that classifies preclinical AD risk (p-tau181-defined) and determine the precision to prospectively estimate 5-year risks of cognitive decline and AD.Discussion: This study will establish the precision of TAS Test to identify preclinical AD and estimate risk of cognitive decline and AD. If accurate, TAS Test will provide a low-cost, accessible enrichment strategy to pre-screen individuals for their likelihood of AD pathology prior to more expensive tests such as blood or imaging biomarkers. This would have wide applications in public health initiatives and clinical trials.Trial Registration: ClinicalTrials.gov Identifier: NCT05194787 , 18 January 2022. Retrospectively registered. [ABSTRACT FROM AUTHOR]

Dementia is a global public health priority and risk reduction is an important pillar of the public health response. While 40% of cases are estimated to be attributable to modifiable health and lifestyle risk factors, public awareness of the evidence is low, limiting peoples' opportunity to adopt risk-reducing behaviours. To address this gap, we designed, implemented, and evaluated an educational intervention, the Preventing Dementia Massive Open Online Course (PDMOOC). This mixed-methods study examined the reach and impact of the free and globally available PDMOOC, to assess its potential to provide effective dementia risk reduction education to a broad international audience. Over 100,000 individuals participated in the PDMOOC across seven iterations from 2016 to 2020, with 55,739 of these consenting to participate in research. Their mean age was 49 years (SD = 15), they came from 167 different countries, and the majority were female (86%), had completed post-secondary education (77%), lived in high-income countries (93%) and worked in health care and social assistance (63%). This demographic profile changed across time, with more men, people with higher education and people from low- and middle-income countries participating in recent course iterations. Two-thirds of participants completed the PDMOOC; completion was associated with being aged 50 to 70 years, residing in a high-income country, having tertiary education, and working in the health sector. Participants reported high levels of satisfaction with the PDMOOC, improved dementia risk reduction understanding and self-efficacy, increased motivation to maintain healthy lifestyles, and, importantly, application of their learning to health behaviour change with the potential to reduce their dementia risk. The PDMOOC educated a large global audience about dementia risk reduction, which contributed to participants making risk-reducing behaviour changes. This suggests MOOCs can be a successful public health strategy to improve dementia risk reduction understanding. [ABSTRACT FROM AUTHOR]

The pathological hallmarks of Alzheimer's disease (AD) include β-amyloid (Aβ) plaques, dystrophic neurites and neurofibrillary pathology, which eventually result in the degeneration of neurons and subsequent dementia. In 1999, international interest in a new therapeutic approach to the treatment of AD was ignited following transgenic mouse studies that indicated that it might be possible to immunise against the pathological alterations in Aβ that lead to aggregation of this protein in the brain. A subsequent phase I human trial for safety, tolerability and immunogenicity using an active immunisation strategy against Aβ had a positive outcome. However, phase IIA human trials involving active immunisation were halted following the diagnosis of aseptic meningoencephalitis in 6% of immunised subjects. Research into immunisation strategies involving transgenic AD mouse models has subsequently been refocused to determine the mechanisms by which plaque clearance and reduced memory deficits are attained, and to establish safer therapeutic approaches that may reduce potentially harmful brain inflammation. The vigour of international research on immunotherapy for AD provides significant hope for a strong therapeutic lead for the escalating number of individuals who will develop this otherwise incurable condition. [ABSTRACT FROM AUTHOR]

A prevailing view in neuroscience is that the mature CNS has relatively little capacity to respond adaptively to injury. Recent data indicating a high degree of structural plasticity in the adult brain provides an impetus to reexamine how central neurons react to trauma. An analysis of both in vivo and in vitro experimental studies demonstrates that certain brain neurons may have an intrinsic ability to respond to structural injury by an attempt at regenerative sprouting. Indeed, aberrant sprouting following neuronal injury may be the cause of epilepsy following brain trauma and may underlie the neuronal changes stimulated by plaque formation in Alzheimer's disease. An understanding of the stereotypical reaction to injury of different CNS neurons, as well as the role of nonneuronal cells, may provide new avenues for therapeutic intervention for a range of neurodegenerative diseases and "acquired" forms of CNS injury. [ABSTRACT FROM AUTHOR]

Mutations in presenilin-1 (PS-1) account for the majority of familial Alzheimer''s disease (AD). While increasing Abeta42 is one mechanism whereby PS-1 mutations are thought to exert their pathogenic effect, little is known about the role of tau in PS-1 AD. This study compares staining (AT8 and tau-2), morphology and quantity of tau-immunoreactive cortical plaques in six PS-1 and five sporadic AD cases. The densities of tau-positive plaques differentiated PS-1 from sporadic AD cases. All PS-1 cases demonstrated a greater than 6-fold increase in tau-2-positive plaques. In PS-1 cases with mutations in exons 5 and 6, there was an increase in classical AD plaques containing hyperphosphorylated tau (AT8- and tau 2-positive). However, cases with exon 8 and 9 mutations had numerous cotton wool plaques containing nonhyperphosphorylated tau (tau-2-positive, AT8-negative). These findings suggest that PS-1 mutations increase tau deposition while mutation-specific cellular responses determine phosphorylation events and may influence cell death mechanisms. [Copyright &y& Elsevier]

The calcium binding protein parvalbumin is expressed in interneurons of two main morphologies, the basket and chandelier cells, which target perisomatic domains on principal cells and are extensively interconnected in laminar networks by synapses and gap junctions. Beyond its utility as a convenient cellular marker, parvalbumin is an unambiguous identifier of the key role that these interneurons play in the fundamental functions of the cortex. They provide a temporal framework for principal cell activity by propagating gamma oscillation, providing coherence for cortical information processing and the basis for timing-dependent plasticity processes. As these parvalbumin networks mature, they are physically and functionally stabilised by axonal myelination and development of the extracellular matrix structure termed the perineuronal net. This maturation correlates with the emergence of high-speed, highly energetic activity and provides a coherent foundation for the unique ability of the cortex to cross-correlate activity across sensory modes and internal representations. [ABSTRACT FROM AUTHOR]

Resting-state functional magnetic resonance imaging measures pathological alterations in neurodegenerative diseases, including Alzheimer's disease. Disruption in functional connectivity may be a potential biomarker of ageing and early brain changes associated with AD-related genes, such as APOE and BDNF. The objective of this study was to identify group differences in resting-state networks between individuals with BDNF Val66Met and APOE polymorphisms in cognitively healthy older persons. Dual regression following Independent Components Analysis were performed to examine differences associated with these polymorphisms. APOE ε3 homozygotes showed stronger functional connectivity than APOE ε4 carriers. Males showed stronger functional connectivity between the Default Mode Network (DMN) and grey matter premotor cortex, while females showed stronger functional connectivity between the executive network and lateral occipital cortex and parahippocampal gyrus. Additionally, we found that with increasing cognitive reserve, functional connectivity increased within the Dorsal Attention Network (DAN), but decreased within the DMN. Interaction effects indicated stronger functional connectivity in Met/ε3 carriers than in Met/ε4 and Val/ε4 within both the DMN and DAN. APOE/BDNF interactions may therefore influence the integrity of functional brain connections in older adults, and may underlie a vulnerable phenotype for subsequent Alzheimer's-type dementia. [ABSTRACT FROM AUTHOR]

Environmentally enriched housing conditions can increase performance on cognitive tasks in APP/PS1 mice; however, the potential effects of environmental enrichment (EE) on disease modification in terms of pathological change are inconclusive. We hypothesized that previous contrasting findings may be attributable to regional differences in susceptibility to amyloid beta (Aβ) plaque deposition in cortical regions that are functionally associated with EE. We characterized fibrillar plaque deposition in 6, 12, and 18–22 months old APP/PS1 mice in the prefrontal (PFC), somatosensory (SS2), and primary motor cortex (M1). We found a significant increase in plaque load between 6 and 12 months in all regions. In animals over 12 months, only the PFC region continued to significantly accumulate plaques. Additionally, 12 months old animals subjected to 6 months of EE showed improved spatial navigation and had significantly fewer plaques in M1 and SS2, but not in the PFC. These findings suggest that the PFC region is selectively susceptible to Aβ deposition and less responsive to the attenuating effects of EE. In contrast, M1 and SS2 regions plateau with respect to Aβ deposition by 12 months of age and are susceptible to amyloid pathology modification by midlife EE. [ABSTRACT FROM AUTHOR]

Background& Aims: Dual-task walking is an emerging marker of cognitive impairment. However, there is uncertainty regarding which dual-task test and measure to use. The aims of this study were to determine the association between three different dual-tasks and 1) global cognition and 2) individual cognitive domains.Methods: Participants (n = 91) were adults aged between 56-83 years (mean 68.8, SD 6.7). Under single- and dual-task, gait speed was obtained using a computerized mat. For the dual-task there were three conditions: 1) reciting alternate letters of the alphabet (DT-alpha); 2) counting backwards in 3 s (DT-counting); and 3) recalling words from a shopping list (DT-recall). Dual-task interference in gait and cognition were calculated as: (dual task-single task)/single task×100 and summed to obtain total interference. The cognitive domains of executive function, processing speed, working memory, verbal fluency, visuospatial function and verbal memory (recall and recognition) were assessed using a battery of neuropsychological tests. Raw test scores were subjected to principal component analysis to derive a global cognition score. Partial correlations were used to determine the strength of associations between single- and dual-task measures and cognitive scores, adjusting for age, sex and education.Results: The strongest significant associations for each cognitive outcome variable were between greater total interference under DT-alpha and lower global cognition (r = 0.25), working memory (r = 0.28) and verbal memory [recognition] (r = 0.21), greater gait interference under DT-alpha and slower processing speed (r = 0.43) and single-task gait speed and verbal fluency (r = 0.23). Associations between dual-task measures and cognition were generally weaker under the DT-counting and DT-recall.Significance: Calculating total and gait interference during DT-alpha may be the most useful in order to identify adults with poorer cognition. [ABSTRACT FROM AUTHOR]

Axon degeneration and axonal loss is a feature of neurodegenerative disease and injury and occurs via programmed pathways that are distinct from cell death pathways. While the pathways of axonal loss following axon severing are well described, less is known about axonal loss following other neurodegenerative insults. Here we use primary mouse cortical neuron cultures grown in compartmentalized chambers to investigate the role of calcium in the degeneration of axons that occurs following a somal insult by the excitotoxin kainic acid. Calcium influx has been implicated in both excitotoxicity and axon degeneration mechanisms, however the link between a somal insult and axonal calcium increase is unclear. Live imaging of axons demonstrated that pharmacologically preventing intracellular calcium increases through the endoplasmic reticulum or mitochondria significantly (p < 0.05) reduced axon degeneration. Live calcium‐imaging with the Ca2+ indicator Fluo‐4 demonstrated that kainic acid exposure to the soma resulted in a rapid, and transient, increase in calcium in the axon, which occured even at low kainic acid concentrations that do not cause axon degeneration within 24 h. However, this calcium transient was followed by a gradual increase in axonal calcium, which was associated with axonal loss. Furthermore, treatment with a range of doses of the microtubule stabilizing drug taxol, which protects against axon fragmentation in this model, prevented this gradual calcium increase, suggesting that the intra‐axonal calcium changes are downstream of microtubule associated events. Biochemical analysis of taxol treated neurons demonstrated a shift in microtubule post‐translational modifications, with a significant (p < 0.05) increase in acetylated tubulin and a significant (p < 0.05) decrease in tyrosinated tubulin, suggestive of a more stable microtubule pool. Together our results suggest that axonal degeneration following excitotoxicity is dependent on an increase in axonal calcium, which is downstream of a microtubule‐dependent event. [ABSTRACT FROM AUTHOR]

Traumatic brain injury (TBI) can cause persistent cognitive changes and ongoing neurodegeneration in the brain. Accumulating epidemiological and pathological evidence implicates TBI in the development of Alzheimer's disease, the most common cause of dementia. Further, the TBI-induced form of dementia, called chronic traumatic encephalopathy, shares many pathological hallmarks present in multiple different diseases which cause dementia. The inflammatory and neuritic responses to TBI and dementia overlap, indicating that they may share common pathological mechanisms and that TBI may ultimately cause a pathological cascade culminating in the development of dementia. This review explores Australian pre-clinical research investigating the pathological links between TBI and dementia. [ABSTRACT FROM AUTHOR]

Cognitive reserve (CR) is a theoretical construct describing the underlying cognitive capacity of an individual that confers differential levels of resistance to, and recovery from, brain injuries of various types. To date, estimates of an individual's level of CR have been based on single proxy measures that are retrospective and static in nature. To develop a measure of dynamic change in CR across a lifetime, we previously identified a latent factor, derived from an exploratory factor analysis of a large sample of healthy older adults, as current CR (cCR). In the present study, we examined the longitudinal results of a sample of 272 older adults enrolled in the Tasmanian Healthy Brain Project. Using results from 12-month and 24-month reassessments, we examined the longitudinal validity of the cCR factor using confirmatory factor analyses. The results of these analyses indicate that the cCR factor structure is longitudinally stable. These results, in conjunction with recent results from our group demonstrating dynamic increases in cCR over time in older adults undertaking further education, lend weight to this cCR measure being a valid estimate of dynamic change in CR over time. [ABSTRACT FROM AUTHOR]

Traumatic brain injury (TBI) has been identified as a risk factor for Alzheimer's disease (AD). However, how such neural damage contributes to AD pathology remains unclear; specifically, the relationship between the timing of a TBI relative to aging and the onset of AD pathology is not known. In this study, we have examined the effect of TBI on subsequent beta-amyloid (Aβ) deposition in APP/PS1 (APPSWE/PSEN1dE9) transgenic mice either before (3 months of age) or after the onset (6 months of age) of plaque pathology. Lateral fluid percussion injury (LFPI), a model of diffuse brain injury, was induced in APP/PS1 and C57Bl/6 wild-type (WT) littermates. LFPI caused a significant increase in both total (p < 0.001) and fibrillar (p < 0.001) Aβ plaque load in the cortex of 3-month-old APP/PS1 mice compared to sham-treated mice at 30 days post-injury. However, in the cortex of 6-month-old mice at 30 days post-injury, LFPI caused a significant decrease in total (p < 0.01), but not fibrillar (p > 0.05), Aβ plaque load compared to sham-treated mice. No Aβ plaques were present in any WT mice across these conditions. Glial fibrillary acidic protein immunolabeling of astrocytes and ionized calcium-binding adapter molecule 1 immunolabeling of microglial/macrophages was not significantly different (p < 0.05) in injured animals compared to sham mice, or APP/PS1 mice compared to WT mice. The current data indicate that TBI may have differential effects on Aβ plaque deposition depending on the age and the stage of amyloidosis at the time of injury. [ABSTRACT FROM AUTHOR]

Environmental enrichment (EE) has been consistently reported to enhance cognitive function in mouse models of neuropathology. Microglia, implicated in Alzheimer's disease pathology, may mediate this effect. The aim of the present study was to investigate the effect of EE on cognitive function and microglia in mouse models of aging and amyloidosis. Male wild-type (Wt) and APP/PS1 mice were randomly assigned to standard housing (SH) or EE from 12 to 18 months of age. Spatial memory testing was performed using the Y and Barnes maze. Immunohistochemical analysis of Aβ load, Iba1 and CD-68-labeled (phagocytic-type) microglia was examined between conditions. EE from 12 months of age was associated with improved short-term memory performance in APP/PS1 mice, despite no reductions to Aβ load. APP/PS1 mice in SH had significantly increased microglia occupying the neocortex and hippocampus (p = 0.02; p = 0.004, respectively) relative to Wt animals. Microglia labeling was not statistically different between EE-exposed APP/PS1 compared to Wt mice, indicating that EE may attenuate the increased microglial load in aging APP/PS1 mice. APP/PS1 mice from EE had significantly (p = 0.01) higher colocalization of Iba1 and CD-68 labeling, indicative of increased phagocytic microglia compared to mice from SH. The findings of the present study suggest that EE after substantial brain amyloidosis, has the potential to preserve domains of cognitive function, while having no effect on Aβ deposition. The current study demonstrates that EE may attenuate microglia in aging APP/PS1 mice, and may promote alterations in cellular phenotype. • Late-life EE was associated with improved short-term memory performance. • Increased microglia in neocortex and hippocampus in APP/PS1 mice was maintained in SH conditions but not EE. • In APP/PS1 animals, EE was associated with increased co-localisation of Iba1 and CD-68 in microglia. [ABSTRACT FROM AUTHOR]

The low expression Met allele of the BDNF Val66Met polymorphism is associated with impaired fear extinction in healthy controls, and poorer response to exposure therapy in patients with Posttraumatic Stress Disorder (PTSD). Given that fear extinction underlies exposure therapy, this raises the question of the impact of BDNFVal66Met polymorphism on fear extinction in PTSD, yet this question has not yet been examined. One hundred and six participants (22 PTSD, 46 trauma-exposed controls (TC) and 38 non-trauma exposed controls (NTC)) completed a fear conditioning and extinction task and saliva samples were taken for DNA extraction and genotyped for the BDNF Val66Met polymorphism. Moderation analyses using PROCESS examined whether BDNF genotype (Val–Val vs Met carriers) moderated the relationship between PTSD symptom severity (and diagnostic status) and skin conductance response (SCR) amplitude during fear extinction. The PTSD group displayed significantly slower fear extinction learning compared to TC and NTC in the early extinction phase. The BDNF Val66Met polymorphism moderated the relationship between PTSD and fear extinction learning, such that poorer fear extinction learning was associated with greater PTSD symptom severity (and PTSD diagnostic status) in individuals with the low-expression Met allele, but no relationship was demonstrated in individuals with the Val–Val allele. This study reveals that impaired fear extinction learning is particularly evident in individuals with PTSD who carry the low-expression BDNF Met allele and importantly not in those with the Val–Val allele. This provides novel evidence of a link between BDNF and impaired fear extinction learning in PTSD, which may contribute to poorer response to exposure therapy. [ABSTRACT FROM AUTHOR]

Early-life cognitive enrichment may reduce the risk of experiencing cognitive deterioration and dementia in later-life. However, an intervention to prevent or delay dementia is likely to be taken up in mid to later-life. Hence, we investigated the effects of environmental enrichment in wildtype mice and in a mouse model of Aβ neuropathology (APPSWE/PS1dE9) from 6 months of age. After 6 months of housing in standard laboratory cages, APPSWE/PS1dE9 ( n = 27) and healthy wildtype ( n = 21) mice were randomly assigned to either enriched or standard housing. At 12 months of age, wildtype mice showed altered synaptic protein levels and relatively superior cognitive performance afforded by environmental enrichment. Environmental enrichment was not associated with alterations to Aβ plaque pathology in the neocortex or hippocampus of APPSWE/PS1dE9 mice. However, a significant increase in synaptophysin immunolabeled puncta in the hippocampal subregion, CA1, in APPSWE/PS1dE9 mice was detected, with no significant synaptic density changes observed in CA3, or the Fr2 region of the prefrontal cortex. Moreover, a significant increase in hippocampal BDNF was detected in APPSWE/PS1dE9 mice exposed to EE, however, no changes were detected in neocortex or between Wt animals. These results demonstrate that mid to later-life cognitive enrichment has the potential to promote synaptic and cognitive health in ageing, and to enhance compensatory capacity for synaptic connectivity in pathological ageing associated with Aβ deposition. [ABSTRACT FROM AUTHOR]

The APP-PS1ΔE9 mouse model of Alzheimer’s disease (AD) exhibits age dependent amyloid β (Aβ) plaque formation in their central nervous system due to high expression of mutated human APP and PSEN1 transgenes. Here we evaluated Aβ deposition and changes in soluble Aβ accumulation in the retinas of aged APP-PS1 mice using a combination of immunofluorescence, retinal flat mounts and western blotting techniques. Aβ accumulation in the retina has previously been shown to be associated with retinal ganglion cell apoptosis in animal models of glaucoma. This study investigated changes in the inner retinal function and structure in APP-PS1 mice using electrophysiology and histological approaches respectively. We report for the first time a significant decline in scotopic threshold response (STR) amplitudes which represents inner retinal function in transgenic animals compared to the wild type counterparts (p < 0.0001). Thinning of the retina particularly involving inner retinal layers and reduction in axonal density in the optic nerve was also observed. TUNEL staining was performed to examine neuronal apoptosis in the inner retina. Intraocular pressure (IOP) measurements showed that APP-PS1ΔE9 mice had a slightly elevated IOP, but the significance of this finding is not yet known. Together, these results substantiate previous observations and highlight that APP-PS1ΔE9 mice show evidence of molecular, functional and morphological degenerative changes in the inner retina. [ABSTRACT FROM AUTHOR]

The Cambridge Neuropsychological Test Automated Battery (CANTAB) is a semiautomated computer interface for assessing cognitive function. We examined whether CANTAB tests measured specific cognitive functions, using established neuropsychological tests as a reference point. A sample of 500 healthy older (M = 60.28 years, SD = 6.75) participants in the Tasmanian Healthy Brain Project completed battery of CANTAB subtests and standard paper-based neuropsychological tests. Confirmatory factor analysis identified four factors: processing speed, verbal ability, episodic memory, and working memory. However, CANTAB tests did not consistently load onto the cognitive domain factors derived from traditional measures of the same function. These results indicate that five of the six CANTAB subtests examined did not load onto single cognitive functions. These CANTAB tests may lack the sensitivity to measure discrete cognitive functions in healthy populations or may measure other cognitive domains not included in the traditional neuropsychological battery. [ABSTRACT FROM AUTHOR]

Amyotrophic lateral sclerosis (ALS) is an adult onset neurodegenerative disease that results in motor dysfunction and death, generally from respiratory failure. 90% of ALS cases are sporadic with no known cause. Familial cases have been linked with mutations in several disparate classes of genes, including those involved in DNA/RNA metabolism, protein misfolding, oxidative stress and the cytoskeleton, leading to the proposition that ALS could be a multi-factorial disease. However, alterations in excitability have been reported in all types of ALS cases, and may be a common disease mechanism predisposing neurons to degeneration. Excitotoxicity has long been suspected as a mediator in the disease process, and may arise from changes in synaptic inputs, or alterations in the excitability of the neurons being stimulated. Although the glutamatergic system is widely recognised as a therapeutic avenue with the potential to extend lifespan and delay disease onset, the causes of altered excitability in ALS are currently unclear and warrant further investigation. This article reviews current evidence of alterations to excitatory and inhibitory signalling in the cortex and spinal cord, and in the intrinsic excitability of motor neurons, in ALS. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is a progressive neurodegenerative disease associated with the loss of cognitive function. Neurofilament (NF) triplet proteins, the major structural (intermediate filament) proteins of neurons, are expressed in a subset of pyramidal cells that show a high degree of vulnerability to degeneration in AD. Alterations in the NF triplet proteins in amyloid-beta (Aβ) plaque-associated dystrophic neurites (DNs) represent the first cytoskeletal aberration to occur in the neocortex in the earliest stages of AD. We generated transgenic APP/PS1 (APPswe/PSEN1dE9) mice on the neurofilament light knockout (NFL KO) background to explore the role of NFL deletion in the context of DN formation, synaptic changes, and other neuropathologic features. Our analysis demonstrated that NFL deficiency significantly increased neocortical DN pathology, Aβ deposition, synapse vulnerability, and microgliosis in APP/PS1 mice. Thus, NFs may have a role in protecting neurites from dystrophy and in regulating cellular pathways related to the generation of Aβ plaques. [ABSTRACT FROM AUTHOR]

Introduction: A majority of familial frontotemporal lobar dementia and amyotrophic lateral sclerosis cases are associated with a large repeat expansion in a non-coding region of the C9ORF72 gene. Currently, little is known about the normal function and the expression pattern of the C9ORF72 protein. The aims of this study were to characterize the expression pattern and cellular localization of the three reported mouse isoforms of C9orf72, over a developmental time-course in primary cultured cortical neurons and brain tissue from C57BL/6 mice. Results: We demonstrated that the different isoforms of C9ORF72 at the mRNA and protein level undergo alterations in expression during development and into adulthood. Cellular fractionation and immunofluorescence demonstrated that levels of nuclear and cytoplasmic expression of isoforms changed significantly over the time course. Additionally, immunofluorescence studies showed C9ORF72 labeling as puncta throughout neurons, extending beyond the microtubule cytoskeleton into actin-rich structures such as filopodia and growth cones. Finally, synaptosome preparations demonstrated the presence of C9ORF72 isoform 1 in synaptic-rich fractions from adult mouse brain. Conclusion: In summary, the presence of C9ORF72 as puncta and within synaptic-rich fractions may indicate involvement at the synapse and differential expression of isoforms in nuclei and cytoplasm may suggest distinct roles for the isoforms. Determining the physiological role of C9ORF72 protein may help to determine the role it plays in disease. [ABSTRACT FROM AUTHOR]

The association between level of educational attainment and cognitive performance is well studied. People with higher education perform better across a broad range of cognitive tasks. However, there is uncertainty as to whether education moderates the trajectory of age-related cognitive decline. This review paper addresses the potential link between education and age-related cognitive decline by evaluating relevant research published since 2000. Studies reporting data on education and its association with the rate of cognitive decline across various cognitive domains were reviewed. A total of 10 studies were identified with a mean follow-up period of 7.6 years; each contained a population-based, non-demented sample. In the majority of studies, results showed that education did not moderate age-associated cognitive decline. The few studies that did find an association between education and decline in specific cognitive functions should be interpreted with caution because of methodological issues. The literature reveals little consistent evidence that normal age-related cognitive decline is moderated by education attainment. This supports a passive theory of cognitive reserve: people with a higher level of education will continue to perform at a higher level of cognitive functioning than their lower educated peers, which may delay the onset of impairment in the future. [ABSTRACT FROM AUTHOR]

Traumatic brain injury is a risk factor for Alzheimer's disease (AD), however the effect of such neural damage on the onset and progression of beta-amyloid (Aβ) plaque pathology is not well understood. This study utilized an in vivo model of focal brain injury to examine how localized damage may acutely affect the onset and progression of Aβ plaque deposition as well as inflammatory and synaptic changes, in the APP/PS1 (APP SWE , PSEN1dE9) transgenic model of AD relative to wild-type (Wt) mice. Acute focal brain injury in 3- and 9-month-old APP/PS1 and Wt mice was induced by insertion of a needle into the somatosensory neocortex, as compared to sham surgery, and examined at 24 h and 7 d post-injury (PI). Focal brain injury did not induce thioflavine-S stained or (pan-Aβ antibody) MOAB-2-labeled plaques at either 24 h or 7 d PI in 3-month-old APP/PS1 mice or Wt mice. Nine-month-old APP/PS1 mice demonstrate cortical Aβ plaques but focal injury had no statistically significant (p > 0.05) effect on thioflavine-S or MOAB-2 plaque load surrounding the injury site at 24 h PI or 7 d PI. There was a significant (p < 0.001) increase in cross-sectional cortical area occupied by Iba-1 positive microglia in injured mice compared to sham animals, however this response did not differ between APP/PS1 and Wt mice (p > 0.05). For both Wt and APP/PS1 mice alike, synaptophysin puncta near the injury site were significantly reduced 24 h PI (compared to sites distant to the injury and the corresponding area in sham mice; p < 0.01), but not after 7 d PI (p > 0.05). There was no significant effect of genotype on this response (p > 0.05). These results indicate that focal brain injury and the associated microglial response do not acutely alter Aβ plaque deposition in the APP/PS1 mouse model. Furthermore the current study demonstrated that the brains of both Wt and APP/PS1 mice are capable of recovering lost synaptophysin immunoreactivity post-injury, the latter in the presence of Aβ plaque pathology that causes synaptic degeneration. [ABSTRACT FROM AUTHOR]

Multiple system atrophy (MSA) exhibits widespread astrogliosis together with α-synuclein (α-syn) glial cytoplasmic inclusions (GCIs) in mature oligodendrocytes. We quantified astrocyte activation by morphometric analysis of MSA cases, and investigated the correlation to GCI proximity. Using Imaris software, we obtained “skinned” three-dimensional models of GFAP-positive astrocytes in MSA and control tissue (n = 75) from confocal z-stacks and measured the astrocyte process length and thickness and radial distance to the GCI. Astrocytes proximal to GCI-containing oligodendrocytes (r < 25 μm) had significantly (p, 0.05) longer and thicker processes characteristic of activation than distal astrocytes (r > 25 μm), with a reciprocal linear correlation (m, 90 μm 2 ) between mean process length and radial distance to the nearest GCI ( R 2 , 0.7). In primary cell culture studies, α-syn addition caused ERK-dependent activation of rat astrocytes and perinuclear α-syn inclusions in mature (MOSP-positive) rat oligodendrocytes. Activated astrocytes were also observed in close proximity to α-syn deposits in a unilateral rotenone-lesion mouse model. Moreover, unilateral injection of MSA tissue-derived α-syn into the mouse medial forebrain bundle resulted in widespread neuroinflammation in the α-syn-injected, but not sham-injected hemisphere. Taken together, our data suggests that the action of localized concentrations of α-syn may underlie both astrocyte and oligodendrocyte MSA pathological features. [ABSTRACT FROM AUTHOR]

The transactive response DNA-binding protein 43 (TDP-43) has been identified as a neurofilament light ( NF-L ) messenger RNA (mRNA)-binding protein. Abnormally increased levels of TDP-43 are detected in patients with amyotrophic lateral sclerosis and a downregulation of NF-L mRNA. However, links between NF-L and TDP-43 expressions are unclear. In this study, we investigated whether the deficiency of NF-L protein can result in alterations in TDP-43 localization or protein expression and whether this is altered with aging. There was a significant increase in TDP-43 protein levels in the cortex and lumbar spinal cord in 12-month-old NF-L knockout (NF-L KO) mice, compared with wild-type (WT) C57BL/6 mice. However, there was no difference in either the phosphorylation of TDP-43 between WT and NF-L KO mice or the abnormal mislocalization of TDP-43 to the cytoplasm in NF-L KO animals. Our findings suggest that NF-L protein or mRNA may negatively affect the expression of TDP-43 in the central nervous system. However, altered phosphorylation of TDP-43 may be more highly associated with aging than the levels of TDP-43 expression. [ABSTRACT FROM AUTHOR]

Genetic polymorphisms of apolipoprotein E (APOE) and brain-derived neurotrophic factor (BDNF) have shown inconsistent associations with healthy adult cognitive functions. Recent investigations have suggested that APOE polymorphisms do not contribute to non-pathological cognitive function and that any effect is likely due to prodromal Alzheimer's disease (AD). Similarly, although BDNF Val66Met polymorphisms affect hippocampal morphology and function, associations with learning and/or memory have not always been found. This study sought to determine whether APOE and BDNF polymorphisms were associated, either independently or in combination, with adult cognition. Comprehensive neuropsychological assessments were conducted on 433 older adults, aged 50-79 years (M=62.16, SD=6.81), which yielded measures of episodic memory, working memory, executive function, and language processing. Participants underwent comprehensive neuropsychological assessment to ensure that only cognitively intact individuals comprised the sample. APOE and BDNF polymorphic data were used as predictors in general linear models that assessed composite cognitive domain variables, while covarying for education and age. Although no main effects for APOE or BDNF were found, the analysis identified a significant APOExBDNF interaction that predicted episodic memory performance (p=.02, η²=.02). Post-hoc analyses demonstrated that in BDNF Val homozygotes, the cognitive consequences of APOE polymorphisms were minimal. However, in BDNF Met carriers, the hypothesized beneficial/detrimental effects of APOE polymorphisms were found. Our data show that concurrent consideration of both APOE and BDNF polymorphisms are required in order to witness a cognitive effect in healthy older adults. [ABSTRACT FROM AUTHOR]

Highlights: [•] BDNF polymorphism is associated with complex cognitive activity in young adulthood. [•] BDNF not associated with complex cognitive activities in middle or later life. [•] COMT polymorphism associated with auditory episodic memory. [•] Combination of COMT and BDNF associated with auditory episodic memory. [•] BDNF and COMT while significant were small in effect size. [ABSTRACT FROM AUTHOR]

Abstract: Amyloid-β (Aβ) plaque accumulation in Alzheimer's disease (AD) is associated with glutamatergic synapse loss, but less is known about its effect on inhibitory synapses. Here, we demonstrate that vesicular γ-aminobutyric acid (GABA) transporter (VGAT) presynaptic bouton density is unaffected in human preclinical and end-stage AD and in APP/PS1 transgenic (TG) mice. Conversely, excitatory vesicular glutamate transporter 1 (VGlut1) boutons are significantly reduced in end-stage AD cases and less reduced in preclinical AD cases and TGs. Aged TGs also show reduced protein levels of VGlut1 and synaptophysin but not VGAT or glutamate decarboxylase (GAD). These findings indicate that GABAergic synapses are preserved in human AD and mouse TGs. Synaptosomes isolated from plaque-rich TG cortex had significantly higher GAD activity than those from plaque-free cerebellum or the cortex of wild-type littermates. Using tissue fractionation, this increased activity was localized to glial synaptosomes, suggesting that Aβ plaques stimulate increased astrocyte GABA synthesis. [Copyright &y& Elsevier]

The neurofilament light (NFL) subunit is considered as an obligate subunit polymer for neuronal intermediate filaments comprising the neurofilament (NF) triplet proteins. We examined cytoskeletal protein levels in the cerebral cortex of NFL knockout (KO) mice at postnatal day 4 (P4), 5 months, and 12 months of age compared with age-matched wild-type (WT) mice of a similar genetic background (C57BL/6). The absence of NFL protein resulted in a significant reduction of phosphorylated and dephosphorylated NFs (NF-P, NF-DP), the medium NF subunit (NFM), and the intermediate filament α-internexin (INT) at P4. At 5 months, NF-DP, NFM, and INT remained significantly lower in knockouts. At 12 months, NF-P was again significantly decreased, and INT significantly increased, in KOs compared with wild type. In addition, protein levels of class III neuron-specific β-tubulin and microtubule-associated protein 2 were significantly increased in NFL KO mice at P4, 5 months, and 12 months, whereas β-actin levels were significantly decreased at P4. Immunocytochemical studies demonstrated that NF-DP accumulated abnormally in the perikarya of cortical neurons by 5 months of age in NFL KO mice. Neurons that lacked NF triplet proteins, such as calretinin-immunolabeled nonpyramidal cells, showed no alterations in density or cytoarchitectural distribution in NFL KO mice at 5 months relative to WT mice, although calretinin protein levels were decreased significantly after 12 months in NFL KO mice. These findings suggest that a lack of NFL protein alters the expression of cytoskeletal proteins and disrupts other NF subunits, causing intracellular aggregation but not gross structural changes in cortical neurons or cytoarchitecture. The data also indicate that changes in expression of other cytoskeletal proteins may compensate for decreased NFs. J. Comp. Neurol. 521:1817-1827, 2013. © 2012 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Abstract: Axonal degeneration is a prominent feature of amyotrophic lateral sclerosis (ALS) both in lower motor nerves as well as descending white matter axons in the spinal cord of human patients. Although the pathology of lower motor axonal degeneration has been described in both human ALS and related transgenic animal models, few studies have examined the pathological features of descending axon degeneration, particularly in mouse models of ALS. We have examined the degeneration of white matter tracts in the G93A mutant superoxide dismutase-1 (mSOD1+) mouse spinal cord white matter from 12weeks of age to end-stage disease. In a G93A mSOD1 mouse model where green fluorescent protein was expressed in neurons (mSOD1+/GFP+), degeneration of white matter tracts was present from the ventral to dorsolateral funiculi. This pattern of axonal pathology occurred from 16weeks of age. However, the dorsal funiculus, the site of the major corticospinal tract in mice, showed relatively less degeneration. Immunohistochemical analysis demonstrated that the neurofilament light chain (NFL) and neuronal intermediate filament protein alpha-internexin accumulated in axon swellings in the spinal white matter. Increased levels of alpha-internexin protein, in mSOD1+ mouse spinal cord tissue, were demonstrated by Western blotting. In contrast, degenerating axons did not show obvious accumulations of neurofilament medium and heavy chain proteins (NFM and NFH). These data suggest that white matter degeneration in this mouse model of ALS is widespread and involves a specific molecular signature, particularly the accumulation of NFL and alpha-internexin proteins. [Copyright &y& Elsevier]

Background: Organotypic brain slice culturing techniques are extensively used in a wide range of experimental procedures and are particularly useful in providing mechanistic insights into neurological disorders or injury. The cellular and morphological alterations associated with hippocampal brain slice cultures has been well established, however, the neuronal response of mouse cortical neurons to culture is not well documented. Methods: In the current study, we compared the cell viability, as well as phenotypic and protein expression changes in cortical neurons, in whole brain slice cultures from mouse neonates (P4-6), adolescent animals (P25-28) and mature adults (P50+). Cultures were prepared using the membrane interface method. Results: Propidium iodide labeling of nuclei (due to compromised cell membrane) and AlamarBlueTM (cell respiration) analysis demonstrated that neonatal tissue was significantly less vulnerable to long-term culture in comparison to the more mature brain tissues. Cultures from P6 animals showed a significant increase in the expression of synaptic markers and a decrease in growth-associated proteins over the entire culture period. However, morphological analysis of organotypic brain slices cultured from neonatal tissue demonstrated that there were substantial changes to neuronal and glial organization within the neocortex, with a distinct loss of cytoarchitectural stratification and increased GFAP expression (p<0.05). Additionally, cultures from neonatal tissue had no glial limitans and, after 14 DIV, displayed substantial cellular protrusions from slice edges, including cells that expressed both glial and neuronal markers. Conclusion: In summary, we present a substantial evaluation of the viability and morphological changes that occur in the neocortex of whole brain tissue cultures, from different ages, over an extended period of culture. [ABSTRACT FROM AUTHOR]

Background: A major pathological hallmark of AD is the deposition of insoluble extracellular β-amyloid (Aβ) plaques. There are compelling data suggesting that Ab aggregation is catalysed by reaction with the metals zinc and copper. Methodology/Principal Findings: We now report that the major human-expressed metallothionein (MT) subtype, MT-2A, is capable of preventing the in vitro copper-mediated aggregation of Aβ1-40 and Aβ1-42. This action of MT-2A appears to involve a metal-swap between Zn7MT-2A and Cu(II)-Ab, since neither Cu10MT-2A or carboxymethylated MT-2A blocked Cu(II)-Aβ aggregation. Furthermore, Zn7MT-2A blocked Cu(II)-Aβ induced changes in ionic homeostasis and subsequent neurotoxicity of cultured cortical neurons. Conclusions/Significance: These results indicate that MTs of the type represented by MT-2A are capable of protecting against Ab aggregation and toxicity. Given the recent interest in metal-chelation therapies for AD that remove metal from Ab leaving a metal-free Aβ that can readily bind metals again, we believe that MT-2A might represent a different therapeutic approach as the metal exchange between MT and Aβ leaves the Ab in a Zn-bound, relatively inert form. [ABSTRACT FROM AUTHOR]

We have investigated alterations in myelin associated with Aβ plaques, a major pathological hallmark of Alzheimer’s disease (AD), in human tissue and relevant transgenic mice models. Using quantitative morphological techniques, we determined that fibrillar Aβ pathology in the grey matter of the neocortex was associated with focal demyelination in human presenilin-1 familial, sporadic and preclinical AD cases, as well as in two mouse transgenic models of AD, compared with age-matched control tissue. This demyelination was most pronounced at the core of Aβ plaques. Furthermore, we found a focal loss of oligodendrocytes in sporadic and preclinical AD cases associated with Aβ plaque cores. In human and transgenic mice alike, plaque-free neocortical regions showed no significant demyelination or oligodendrocyte loss compared with controls. Dystrophic neurites associated with the plaques were also demyelinated. We suggest that such plaque-associated focal demyelination of the cortical grey matter might impair cortical processing, and may also be associated with aberrant axonal sprouting that underlies dystrophic neurite formation. [ABSTRACT FROM AUTHOR]