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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 (APPSWE, 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 24h and 7d post-injury (PI). Focal brain injury did not induce thioflavine-S stained or (pan-Aβ antibody) MOAB-2-labeled plaques at either 24h or 7d 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 24h PI or 7d 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 24h PI (compared to sites distant to the injury and the corresponding area in sham mice; p<0.01), but not after 7d 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., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Accumulating evidence indicates that damage to the adult mammalian brain evokes an array of adaptive cellular responses and may retain a capacity for structural plasticity. We have investigated the cellular and architectural alterations following focal experimental brain injury, as well as the specific capacity for structural remodeling of neuronal processes in a subset of cortical interneurons. Focal acute injury was induced by transient insertion of a needle into the neocortex of anesthetized adult male Hooded-Wistar rats and thy1 green fluorescent protein (GFP) mice. Immunohistochemical, electron microscopy, and bromodeoxyuridine cell proliferation studies demonstrated an active and evolving response of the brain to injury, indicating astrocytic but not neuronal proliferation. Immunolabeling for the neuron-specific markers phosphorylated neurofilaments, α-internexin and calretinin at 7 days post injury (DPI) indicated phosphorylated neurofilaments and α-internexin but not calretinin immunopositive axonal sprouts within the injury site. However, quantitative studies indicated a significant realignment of horizontally projecting dendrites of calretinin-labeled interneurons at 14 DPI. This remodeling was specific to calretinin immunopositive interneurons and did not occur in a subpopulation of pyramidal neurons expressing GFP in the injured mouse cortex. These data show that subclasses of cortical interneurons are capable of adaptive structural remodeling.

A number of intracellular proteins that are protective after brain injury are classically thought to exert their effect within the expressing cell. The astrocytic metallothioneins (MT) are one example and are thought to act via intracellular free radical scavenging and heavy metal regulation, and in particular zinc. Indeed, we have previously established that astrocytic MTs are required for successful brain healing. Here we provide evidence for a fundamentally different mode of action relying upon intercellular transfer from astrocytes to neurons, which in turn leads to uptake-dependent axonal regeneration. First, we show that MT can be detected within the extracellular fluid of the injured brain, and that cultured astrocytes are capable of actively secreting MT in a regulatable manner. Second, we identify a receptor, megalin, that mediates MT transport into neurons. Third, we directly demonstrate for the first time the transfer of MT from astrocytes to neurons over a specific time course in vitro. Finally, we show that MT is rapidly internalized via the cell bodies of retinal ganglion cells in vivo and is a powerful promoter of axonal regeneration through the inhibitory environment of the completely severed mature optic nerve. Our work suggests that the protective functions of MT in the central nervous system should be widened from a purely astrocytic focus to include extracellular and intra-neuronal roles. This unsuspected action of MT represents a novel paradigm of astrocyte-neuronal interaction after injury and may have implications for the development of MT-based therapeutic agents.

We report a new model of transient axonal stretch injury involving pressurized fluid deflection of bundles of axons, resulting in a transient 1-6% increase in original axon length to investigate the slow progression of axonal alterations that are characteristic of diffuse axonal injury (DAI). We found no discernable difference in axon bundle morphology or cytoskeletal neurofilament protein arrangement between unstretched and stretched axonal bundles at 24 h post-injury. However, by 48 h post-injury, there was a stereotypical response of stretched axons involving characteristic neurofilament alterations that bear similarities to in vivo neuronal responses associated with DAI that have been reported previously. For instance, neurofilament protein immunoreactivity (SMI-312) was increased in axons contained within 51% of all injured axon bundles at 48 h compared to surrounding unstretched axon bundles, suggestive of neurofilament compaction. Furthermore, axonal bundle derangement occurred in 25% of injured axon bundles, with individual fibres segregating from each other and becoming undulating and wavy. By 72 h post-stretch, 70% of injured axon bundles underwent secondary axotomy, becoming completely severed at the site of initial stretch injury. While these results suggest a temporal series of stereotypical responses of axons to injury, we were able to distinguish very clear differences between mildly (100-103% increase in original axonal length) injured and strongly injured (106%+) axons. For instance, mildly injured axons developed increased neurofilament immunoreactivtity (SMI-312) within 48 h, and the marked development of ring-like neurofilament immunoreactive structures within axonal bundles, which were rarely axotomized. Conversely, at more severe strain levels increased neurofilament immunoreactivity was less apparent, while axons often became distorted and disorganised within axonal bundles and eventually became completely disconnected. Almost no ring-like neurofilament structures were observed in these severely injured axonal bundles. This suggests that axons do not respond in a stereotypical manner to a transient stretch insult, and indeed that variable degrees of stretch injury activate different responses within axons, with dramatically different outcomes. Hence, it is possible that the cytoskeletal characteristics that we have used in this study may be useful parameters for discriminating between mildly and severely injured axons following TBI.

This study investigated the role of alpha-internexin in the neuronal alterations associated with beta-amyloid plaque formation in Alzheimer's disease (AD). Cortical neurons could be defined by their variable content of neurofilament (NF) triplet and alpha-internexin proteins, with a distinct population of supragranular pyramidal cells containing alpha-internexin alone. Both NF triplet and alpha-internexin were localized to reactive axonal structures in physically damaged neurons in experimental trauma models. Similarly, NF triplet and alpha-internexin immunoreactive neurites were localized to plaques densely packed with beta-amyloid fibrils in preclinical AD cases, indicating that certain plaques may cause structural injury or impediment of local axonal transport. However, alpha-internexin, and not NF triplet, ring-like reactive neurites were present in end-stage AD cases, indicating the relatively late involvement of neurons that selectively contain alpha-internexin. These results implicate the expression of specific intermediate filament proteins in a distinct hierarchy of differential neuronal vulnerability to AD.

Metallothioneins (MTs) are small cysteine-rich proteins which are found widely throughout the mammalian body, including the CNS. There are extensive data on the structure and expression of MTs, and many basic properties pertinent to MT biology in the CNS appear to be well established. As discussed in this review, one isoform class (MT-I/II) is rapidly induced following many types of CNS insult, and is strongly neuroprotective, whilst another isoform class (MT-III) shows major differences in its expression profile and physiological properties. As in other tissues, there is no clear consensus on the mechanism of MT action in the CNS and how it exerts its protective role, despite a number of excellent animal and cell culture models of MT expression in the brain, and a large literature on the physico-chemical properties of MTs extending over several decades. This review is therefore an attempt to summarise the recent literature on the expression of MTs in the adult mammalian brain and how MTs possibly act to protect the brain following physical or chemical insult. One exciting finding from recent work is that perturbing the levels of MT in the brain has an effect that extends beyond cells which normally express MT to other cell types including neurons, microglia and cells of the immune system. These observations were made mainly using animal models in which MT action can be observed in its normal cellular context, and this review focuses particularly on work conducted in animal models of physical and chemical injury in the brain.

Metallothioneins (MTs) are small, cysteine-rich, metal binding proteins. Their function has often been considered as stress-related proteins capable of protecting cells from heavy metal toxicity and oxidative free radicals. However, recent interest has focused on the brain-specific MT-III isoform, which has neurite-inhibitory properties. To investigate the effect of another MT isoform, human MT-IIA, on neurite growth, we used rat cortical neuron cultures. MT-IIA promoted a significant increase in the rate of initial neurite elongation of individually plated neurons. We also investigated the effect of MT-IIA on the neuronal response to axonal transection in vitro. MT-IIA promoted reactive axonal growth after injury, and, by 18 hr after transection, MT-IIA had promoted axonal growth across the injury tract. Exogenous application of MT-IIA after cortical brain injury promoted wound healing, as observed by a significant decrease in cellular degradation at 4 d after injury. Furthermore, MT-IIA-treated rats exhibited numerous SMI-312-immunoreactive axonal processes within the injury tract. This was in contrast to vehicle-treated animals, in which few axonal sprouts were observed. By 7 d after injury, MT-IIA treatment resulted in a total closing over of the injury tract by microglia, astrocytes, and reactive axonal processes. However, although some reactive axonal processes were observed within the injury tract of vehicle-treated rats, the tract itself was almost never entirely enclosed. These results are discussed in relation to a possible physiological role of metallothioneins in the brain, as well as in a therapeutic context.

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]

J. Neurochem. (2010) 112, 1147–1155. Acute axonal shear and stretch in the brain induces an evolving form of axonopathy and is a major cause of ongoing motor, cognitive and emotional dysfunction. We have utilized an in vitro model of mild axon bundle stretch injury, in cultured primary cortical neurons, to determine potential early critical cellular alterations leading to secondary axonal degeneration. We determined that transient axonal stretch injury induced an initial acute increase in intracellular calcium, principally derived from intracellular stores, which was followed by a delayed increase in calcium over 48 h post-injury (PI). This progressive and persistent increase in intracellular calcium was also associated with increased frequency of spontaneous calcium fluxes as well as cytoskeletal abnormalities. Additionally, at 48 h post-injury, stretch-injured axon bundles demonstrated filopodia-like sprout formation that preceded secondary axotomy and degeneration. Pharmacological inhibition of the calcium-activated phosphatase, calcineurin, resulted in reduced secondary axotomy ( p < 0.05) and increased filopodial sprout length. In summary, these results demonstrate that stretch injury of axons induced an initial substantial release of calcium from intracellular stores with elevated intracellular calcium persisting over 2 days. These long-lasting calcium alterations may provide new insight into the earliest neuronal abnormalities that follow traumatic brain injury as well as the key cellular changes that lead to the development of diffuse axonal injury and secondary degeneration. [ABSTRACT FROM AUTHOR]

Recent data suggests that metallothioneins (MTs) are major neuroprotective proteins within the CNS. In this regard, we have recently demonstrated that MT-IIA (the major human MT-I/-II isoform) promotes neural recovery following focal cortical brain injury. To further investigate the role of MTs in cortical brain injury, MT-I/-II expression was examined in several different experimental models of cortical neuron injury. While MT-I/-II immunoreactivity was not detectable in the uninjured rat neocortex, by 4 days, following a focal cortical brain injury, MT-I/-II was found in astrocytes aligned along the injury site. At latter time points, astrocytes, at a distance up to several hundred microns from the original injury tract, were MT-I/-II immunoreactive. Induced MT-I/-II was found both within the cell body and processes. Using a cortical neuron/astrocyte co-culture model, we observed a similar MT-I/-II response following in vitro injury. Intriguingly, scratch wound injury in pure astrocyte cultures resulted in no change in MT-I/-II expression. This suggests that MT induction was specifically elicited by neuronal injury. Based upon recent reports indicating that MT-I/-II are major neuroprotective proteins within the brain, our results provide further evidence that MT-I/-II plays an important role in the cellular response to neuronal injury. [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]

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]