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The female sex hormone estrogen has been ascribed potent neuroprotective properties. It signals by binding and activating estrogen receptors that, depending on receptor subtype and upstream or downstream effectors, can mediate gene transcription and rapid non-genomic actions. In this way, estrogen receptors in the brain participate in modulating neural differentiation, proliferation, neuroinflammation, cholesterol metabolism, synaptic plasticity, and behavior. Circulating sex hormones decrease in the course of aging, more rapidly at menopause in women, and slower in men. This review will discuss what this drop entails in terms of modulating neuroprotection and resilience in the aging brain downstream of spatiotemporal estrogen receptor alpha (ERα) and beta (ERβ) signaling, as well as in terms of the sex differences observed in Alzheimer’s disease (AD) and Parkinson’s disease (PD). In addition, controversies related to ER expression in the brain will be discussed. Understanding the spatiotemporal signaling of sex hormones in the brain can lead to more personalized prevention strategies or therapies combating neurodegenerative diseases.

Sirtuin 2 (SIRT2) has been proposed to have a central role on aging, inflammation, cancer and neurodegenerative diseases; however, its specific function remains controversial. Recent studies propose SIRT2 pharmacological inhibition as a therapeutic strategy for several neurodegenerative diseases including Alzheimer’s disease (AD). Surprisingly, none of these published studies regarding the potential interest of SIRT2 inhibition has assessed the peripheral adverse side consequences of this treatment. In the present study we demonstrate that pharmacological treatment with 33i improved cognitive dysfunction and LTP, and reduced amyloid pathology and neuroinflammation in the APP/PS1 AD mouse model. However, this treatment increased peripheral levels of inflammatory cytokines IL-1β, Tnf-α, Tgf-β, IL-6 and MCP-1. Accordingly, peripheral SIRT2 inhibition with the blood brain barrier impermeable compound AGK-2, worsened the cognitive capacities and increased systemic inflammation. These results suggest that, although SIRT2 pharmacological inhibition may have beneficial consequences in neurodegenerative diseases, its systemic adverse side effects should be taken into account. This information is essential to maximize the therapeutic potential of SIRT2 inhibition not only for AD but also for other neurodegenerative diseases.

Alzheimer’s disease is a multifactorial disorder with a heterogeneous patient population. Comorbidities such as hypertension, hypercholesterolemia and diabetes are known contributors to the disease progression. Indeed, therapies targeting these disorders have been shown efficient in dementia prevention. However, their mechanistic contribution to Alzheimer’s pathology and neurodegeneration has not been fully clarified.In the current study, we used CSF samples from a memory clinic cohort of 90 patients without diagnosed hypertension, hypercholesterolemia, or diabetes nor other neurodegenerative disorder, to investigate 13 molecular markers representing key mechanisms underlying Alzheimer’s pathogenesis. Levels were compared between clinical groups of subjective cognitive decline, mild cognitive impairment, and Alzheimer’s disease. Associations between markers and groups of markers were analyzed by linear regression. Two-step cluster analysis was used to determine patient clusters. Two key markers were further analyzed by immunofluorescence staining in hippocampus from control and AD individuals without hypertension, hypercholesterolemia nor diabetes.CSF angiotensinogen, thioredoxin-1, and interleukin-15 were the biomarkers with the most prominent associations with Alzheimer’s pathology, synaptic and axonal damage. Synaptosomal-associated protein 25 kDa and neurofilament light chain were increased in mild cognitive impairment and Alzheimer cases. When we grouped biomarkers by biological function, we found that inflammatory and survival components were associated with Alzheimer’s pathology, synaptic dysfunction and axonal damage. Moreover, a vascular/metabolic component was associated with synaptic dysfunction. In data-driven analysis, two patient clusters were identified; Older participants with increased CSF markers of oxidative stress, vascular pathology and neuroinflammation were assigned to cluster 1, that was also smaller and characterized by increased synaptic and axonal damage, compared to individuals in cluster 2. Clinical groups were evenly distributed between the clusters.Analysis of post-mortem hippocampal tissue, showed that, compared to controls, angiotensinogen staining was higher in Alzheimer’s disease and was also found to co-localize with phosphorylated-tau.In a population free of common comorbidities, we could still find associations between Alzheimer’s disease biomarkers and markers of pathways associated with increased risk for Alzheimer’s disease (i.e., neuroinflammation, vascular function, oxidative stress and cholesterol homeostasis), suggesting that these pathways are contributing to Alzheimer’s disease mechanisms even in absence of clinically diagnosed comorbidities. The identification of distinct biomarker-driven endophenotypes of cognitive disorder patients, further highlights the biological heterogeneity of Alzheimer’s disease and the importance of developing tailored prevention and treatment strategies.

Sustained microglial activation and increased pro-inflammatory signalling cause chronic inflammation and neuronal damage in Alzheimer’s disease (AD). Resolution of inflammation follows neutralization of pathogens and is a response to limit damage and promote healing, mediated by pro-resolving lipid mediators (LMs). Since resolution is impaired in AD brains, we decided to test if intranasal administration of pro-resolving LMs in the AppNL-G-F/NL-G-F mouse model for AD could resolve inflammation and ameliorate pathology in the brain. A mixture of the pro-resolving LMs resolvin (Rv) E1, RvD1, RvD2, maresin 1 (MaR1) and neuroprotectin D1 (NPD1) was administered to stimulate their respective receptors. We examined amyloid load, cognition, neuronal network oscillations, glial activation and inflammatory factors. The treatment ameliorated memory deficits accompanied by a restoration of gamma oscillation deficits, together with a dramatic decrease in microglial activation. These findings open potential avenues for therapeutic exploration of pro-resolving LMs in AD, using a non-invasive route.

Oxidative stress and neuroinflammation play a central role in Alzheimer’s Disease (AD) pathogenesis. However, the mechanism by which these processes lead to neurodegeneration is still not fully understood. Thioredoxin-1 (Trx1) is an antioxidant protein that can be cleaved into a peptide known as Thioredoxin-80 (Trx80), which modulates monocyte function in the periphery and shows anti-amyloidogenic properties in the brain. In this study we aimed to further clarify the biological function of this peptide and its regulation in the brain. We show that neurons are the main producers of Trx80 in the brain. Trx80 levels increase in vivo both in normal aging and in young APPNL-G-F mouse model of amyloid pathology. Trx80 levels were increased in neurons in primary culture treated with either rotenone or 27-hydroxycholesterol, what suggests that Trx80 production is stimulated upon oxidative stress. RNA-sequencing followed by differential gene expression analysis revealed that Trx80 induces microglia activation into a phenotype compatible with interferon response microglia. Finally, we determine that the induction of this microglia phenotype by Trx80 is Trem2-dependent. This study identifies Trx80 as a novel neuron-derived signaling mechanism that modulates microglia function under stress conditions. Strategies to regulate Trx80 levels could be beneficial against AD pathology.

Sustained microglial activation and increased pro-inflammatory signalling cause chronic inflammation and neuronal damage in Alzheimer's disease (AD). Resolution of inflammation follows neutralization of pathogens and is a response to limit damage and promote healing, mediated by pro-resolving lipid mediators (LMs). Since resolution is impaired in AD brains, we decided to test if intranasal administration of pro-resolving LMs in the App

Alzheimer's disease (AD) is the most common form of dementia and it is characterized by the deposition of amyloid-β (Aβ) plaques and neurofibrillary tangles in the brain. However, the complete pathogenesis of the disease is still unknown. High level of serum cholesterol has been found to positively correlate with an increased risk of dementia and some studies have reported a decreased prevalence of AD in patients taking cholesterol-lowering drugs. Years of research have shown a strong correlation between blood hypercholesterolemia and AD, however cholesterol is not able to cross the Blood Brain Barrier (BBB) into the brain. Cholesterol lowering therapies have shown mixed results in cognitive performance in AD patients, raising questions of whether brain cholesterol metabolism in the brain should be studied separately from peripheral cholesterol metabolism and what their relationship is. Unlike cholesterol, oxidized cholesterol metabolites known as oxysterols are able to cross the BBB from the circulation into the brain and vice-versa. The main oxysterols present in the circulation are 24S-hydroxycholesterol and 27-hydroxycholesterol. These oxysterols and their catalysing enzymes have been found to be altered in AD brains and there is evidence indicating their influence in the progression of the disease. This review gives a broad perspective on the relationship between hypercholesterolemia and AD, cholesterol lowering therapies for AD patients and the role of oxysterols in pathological and non-pathological conditions. Also, we propose cholesterol metabolites as valuable targets for prevention and alternative AD treatments., We thank the continuous support from Margaretha Af Ugglas Foundation, Stonhes Foundation and Foundation of Old Servants, the Swedish Medical Foundation (SSMF), Lindhés Advokatbyrå AB Foundation, the Karolinska Institutet Foundation for Research, the Swedish Research Council and StratNeuro.

Background: Midlife hypercholesterolemia is a risk factor for dementia, possibly via vascular-related pathways. Another proposed factor linking elevated systemic cholesterol levels and neurodegenerative diseases is the oxidized cholesterol metabolite 27-hydroxycholesterol (27-OH) that is able to pass the blood-brain barrier. High levels of 27-OH harm neuronal integrity and function, yet the effect of high 27-OH levels on oligodendrocyte function remains unexplored. Since abnormal myelin structure results in the disconnection of neural networks that is an early phenomenon in neurodegenerative diseases, this study aimed to determine whether 27-OH affects myelination in the brain. Methods: Effects of 27-OH treatment were investigated both in isolated and co-cultured oligodendrocytes. Transgenic female mice with increased systemic 27-OH levels (Cyp27Tg) underwent behavioural testing and their brains were immunohistochemically stained and lysed for immunoblotting. CSF samples from a memory clinic cohort were analysed for associations between 27-OH and myelin proteins. Results: Whereas human oligodendroglioma cells were resistant to high levels of 27-OH (10 µM), cell death was induced in primary rat oligodendrocytes already at low concentrations (0.5 µM). Long-term effects from treatment with 1 µM 27-OH stimulated differentiation of oligodendrocytes in murine 3D co-cultures. Female Cyp27Tg mice demonstrated learning deficits in the Morris Water Maze compared to non-transgenic littermates. Levels of myelin basic protein were increased in the corpus callosum of Cyp27Tg mice but adenomatous polyposis coli clone 1 (CC1) and platelet-derived growth factor receptor α (PDGFR1α) were unaltered, while levels of myelin oligodendrocyte glycoprotein were decreased in myelin enriched fractions. Levels of 27-OH in the CSF of memory clinic patients were associated with increased levels of the oligodendrogenesis regulating enzyme 2',3'-Cyclic-nucleotide 3'-phosphodiesterase (CNPase; β = 0.38, p = 0.022). Conclusions: The hypercholesterolemia associated 27-OH alters the rate of differentiation from progenitor cells into mature oligodendrocytes and influences oligodendrocyte viability suggesting that 27-OH reduces the oligodendrocytic ability for appropriate remodelling in the ageing brain by reducing the pool of progenitor cells.

Cholesterol turnover and CYP46A1 regulation are reported to be crucial for memory functions. An increasing body of evidence shows that CYP46A1 activation is able to reduce Alzheimer’s Disease (AD) pathological processes. In this study we report for the first time that CYP46A1 overexpression and increase of 24S-hydroxycholesterol (24OH) induces sex-specific changes in synaptic functions in aged mice, being beneficial in females while detrimental in males. The positive effects on cognition in aged CYP46A1 overexpressing female mice were accompanied by morphological changes in dendritic spines and enhancement of estrogen receptor signaling in hippocampus. In aged males, CYP46A1 overexpression leads to anxiety-like behavior and worsening of spatial memory, followed by decreased dendritic spine density and higher 5α-dihydrotestosterone (DHT) levels in hippocampus. Further, analysis of cerebrospinal fluid (CSF) from AD, mild cognitive impairment and healthy patients revealed that 24OH was negatively associated to markers of neurodegeneration in women but not in men. Based on our results, CYP46A1 activation may represent a pharmacological target that could specifically enhance brain estrogen receptor signaling in women at risk of developing AD. Finally, this study highlights the importance of taking into account the sex-dimension in both preclinical and clinical studies of neurodegenerative diseases like AD.

Alterations in cholesterol metabolism in the brain have a major role in the physiology of Alzheimer’s disease (AD). Oxysterols are cholesterol metabolites with multiple implications in memory functions and in neurodegeneration. Previous studies have shown detrimental effects of cholesterol metabolites in neurons, but its effect in glial cells is unknown. We used a high-fat/high-cholesterol diet in mice to study the effects of hypercholesterolemia over the alarmin S100A8 cascade in the hippocampus. Using CYP27Tg, a transgenic mouse model, we show that the hypercholesterolemia influence on the brain is mediated by the excess of 27-hydroxycholesterol (27-OH), a cholesterol metabolite. We also employed an acute model of 27-OH intraventricular injection in the brain to study RAGE and S100A8 response. We used primary cultures of neurons and astrocytes to study the effect of high levels of 27-OH over the S100A8 alarmin cascade. We report that a high-fat/high-cholesterol diet leads to an increase in S100A8 production in the brain. In CYP27Tg, we report an increase of S100A8 and its receptor RAGE in the hippocampus under elevated 27-OH in the brain. Using siRNA, we found that 27-OH upregulation of RAGE in astrocytes and neurons is mediated by the nuclear receptor RXRγ. Silencing RXRγ in neurons prevented 27-OH-mediated upregulation of RAGE. These results show that S100A8 alarmin and RAGE respond to high levels of 27-OH in the brain in both neurons and astrocytes through RXRγ. Our study supports the notion that 27-OH mediates detrimental effects of hypercholesterolemia to the brain via alarmin signaling., Open access funding provided by Karolinska Institute. This research was supported by the following Swedish foundations: Swedish Brain Power, the regional agreement on medical training and clinical research (ALF) between Stockholm County Council and Karolinska Institutet, Strategic Neuroscience Program, Margaretha af Ugglas Foundation, Gun och Bertil Stohnes Stiftelse, Karolinska Institutet fund for geriatric research, Stiftelsen Gamla Tjänarinnor, Demensfonden,Lindhés Advokatbyrå, Hjärnfonden, and Alzheimerfonden. R. L.-V. was fnancially supported by Mexico’s National Council for Science and Technology (CONACYT) CVU, 209252, and by Olle Enqvist Foundation grant no. 2014/778. Ramon Areces Foundation, Spain, supported E. P., EMBO Long-Term Fellowship (ALTF 696–2013), the SSMF postdoctoral fellowship, and Juan de la Cierva-Incorporación. (IJCI-2016–27,658) supported P. M.-S.

The major genetic risk factor for Alzheimer’s disease (AD), apolipoprotein E4 (ApoE4), has been suggested to have detrimental effects on neurons, including direct toxicity via apoptosis. Thioredoxin-1 (Trx1) is an endogenous antioxidant protein important for redox regulation and participates in the regulation of apoptosis through the inhibition of apoptosis signal-regulating kinase-1 (Ask-1). In this study, we have investigated the effects of ApoE on Trx1 in the brain. Our results showed that the protein levels of Trx1 were reduced in the hippocampus of ApoE4 targeted replacement (TR) mice compared to ApoE3 TR mice. The reduction was also seen in vitro after treatment of both human primary cortical neurons and neuroblastoma cells with human recombinant ApoE4 (rApoE4). Furthermore, ApoE4 caused a disruption of lysosomal integrity and a shift in the localization of Cathepsin D, an enzyme known to degrade Trx1. ApoE4 treatment induced in addition apoptosis through translocation of Death-domain associated protein-6 (Daxx) from the nucleus to the cytosol, suggesting an activation of the Ask-1 pathway. This toxicity was prevented by overexpression of Trx1 and other endogenous Ask-1 inhibitors. Our data suggests that down-regulation of Trx1 is involved in the toxicity caused by ApoE4. An activated ASK-1 pathway might indeed make cells more vulnerable to other insults such as amyloid-β, which could partially explain the mechanism behind the strongest genetic risk factor for AD.

Ismail et al. show that 27-hydroxycholesterol, a peripheral cholesterol metabolite capable of passing the blood–brain barrier, reduces brain glucose uptake by upregulating the renin-angiotensin system and inhibiting GLUT4. This alteration affects memory processes and is likely to have implications on neurodegenerative diseases., Hypercholesterolemia is associated with cognitively deteriorated states. Here, we show that excess 27-hydroxycholesterol (27-OH), a cholesterol metabolite passing from the circulation into the brain, reduced in vivo brain glucose uptake, GLUT4 expression, and spatial memory. Furthermore, patients exhibiting higher 27-OH levels had reduced 18F-fluorodeoxyglucose uptake. This interplay between 27-OH and glucose uptake revealed the engagement of the insulin-regulated aminopeptidase (IRAP). 27-OH increased the levels and activity of IRAP, countered the IRAP antagonist angiotensin IV (AngIV)–mediated glucose uptake, and enhanced the levels of the AngIV-degrading enzyme aminopeptidase N (AP-N). These effects were mediated by liver X receptors. Our results reveal a molecular link between cholesterol, brain glucose, and the brain renin-angiotensin system, all of which are affected in some neurodegenerative diseases. Thus, reducing 27-OH levels or inhibiting AP-N maybe a useful strategy in the prevention of the altered glucose metabolism and memory decline in these disorders.

Several studies support the relation between leptin and Alzheimer’s disease (AD). We show that leptin levels in CSF are unchanged as subjects progress to AD. However, in AD hippocampus, leptin signalling was decreased and leptin localization was shifted, being more abundant in reactive astrocytes and less in neurons. Similar translocation of leptin was found in brains from Tg2576 and apoE4 mice. Moreover, an enhancement of leptin receptors was found in hippocampus of young Tg2576 mice and in primary astrocytes and neurons treated with Ab1-42. In contrast, old Tg2576 mice showed decreased leptin receptors levels. Similar findings to those seen in Tg2576 mice were found in apoE4, but not in apoE3 mice. These results suggest that leptin levels are intact, but leptin signalling is impaired in AD. Thus, Ab accumulation and apoE4 genotype result in a transient enhancement of leptin signalling that might lead to a leptin resistance state over time.

Serotonin (5-HT) plays a central role in the integrity of different brain functions. The 5-HT homeostasis is regulated by many factors, including serotonin transporter (SERT), monoamine oxidase enzyme (MAO), and several 5-HT receptors, including the 5-HT1B. There is little knowledge how the dynamics of this system is affected by the amyloid-β (Aβ) burden of Alzheimer's disease (AD) pathology. SH-SY5Y neuroblastoma cells transfected with the amyloid precursor protein (APP) gene containing the Swedish mutations causing familial AD (APPswe), were used as a model to explore the effect of Aβ pathology on 5-HT1B and related molecules including the receptor adaptor protein (p11), SERT and MAOA gene expression, and MAOA activity after treatment with selective serotonin reuptake inhibitor (SSRI) (sertraline), and a 5-HT1B receptor antagonist. Sertraline led more than 70 fold increase of 5-HT1B gene expression (p 0.001), an increased serotonin turnover in both APPswe and control cells and reduced intracellular serotonin levels by 75% in APPswe cells but not in controls (p 0.05). Treatment with the 5-HT1B receptor antagonist increased SERT gene-expression in control cells but not in the APPswe cells. 5-HT and 5-HT1B antagonist treatment resulted in different p11 expression patterns in APPswe cells compared to controls. Although MAOA gene expression was not changed by APPswe overexpression, adding 5-HT lead to a significant increase in MAOA gene expression in APPswe but not control cells. These findings suggest that the sensitivity of the 5-HT1B receptor and related systems is affected by APPswe overexpression, with potential relevance for pharmacologic intervention in AD. This may at least partly explain the lack of effect of SSRIs in patients with AD and depression.

Evidence is accumulating that the main chronic diseases of aging Alzheimer’s disease (AD) and type-2 diabetes mellitus (T2DM) share common pathophysiological mechanisms. This study aimed at applying systems biology approaches to increase the knowledge of the shared molecular pathways underpinnings of AD and T2DM. We analysed transcriptomic data of post-mortem AD and T2DM human brains to obtain disease signatures of AD and T2DM and combined them with protein-protein interaction information to construct two disease-specific networks. The overlapping AD/T2DM network proteins were then used to extract the most representative Gene Ontology biological process terms. The expression of genes identified as relevant was studied in two AD models, 3xTg-AD and ApoE3/ApoE4 targeted replacement mice. The present transcriptomic data analysis revealed a principal role for autophagy in the molecular basis of both AD and T2DM. Our experimental validation in mouse AD models confirmed the role of autophagy-related genes. Among modulated genes, Cyclin-Dependent Kinase Inhibitor 1B, Autophagy Related 16-Like 2, and insulin were highlighted. In conclusion, the present investigation revealed autophagy as the central dys-regulated pathway in highly co-morbid diseases such as AD and T2DM allowing the identification of specific genes potentially involved in disease pathophysiology which could become novel targets for therapeutic intervention.

Background Polypharmacy is common among older adults. However, little is known about the composition of polypharmacy: which are the most frequently used drugs, and how much do these drugs contribute to the overall prevalence of polypharmacy. Methods A total of 822,619 Swedes aged ≥75 years was identified from the Total Population Register. Through record-linkage with the Swedish Prescribed Drug Register and the Social Services Register we could analyze concurrent drug use in the entire population (both individuals living in the community and institution) on the 31 December 2013. Results The prevalence of polypharmacy (≥5 drugs) was 45%. The most frequently used drugs were cardiovascular drugs, analgesics, and psychotropics. By excluding the ten most frequently used drug classes or compounds, the prevalence of polypharmacy was reduced by 69% and 51% respectively. The majority of the users of either one of the 10 most frequently used drugs concurrently used at least 4 other drug classes (66%-85%). Conclusion Almost half of the individuals aged ≥75 years are exposed to polypharmacy in Sweden. A handful of drugs make a large contribution to the overall prevalence of polypharmacy and the majority of drugs prescribed to persons aged ≥75 years are used in combination with other drugs. This highlights the high use of drugs, and the need to consider other concurrent drug treatments when prescribing for older adults.

Hypercholesterolemia is a risk factor for neurodegenerative diseases, but how high blood cholesterol levels are linked to neurodegeneration is still unknown. Here, we show that an excess of the blood–brain barrier permeable cholesterol metabolite 27-hydroxycholesterol (27-OH) impairs neuronal morphology and reduces hippocampal spine density and the levels of the postsynaptic protein PSD95. Dendritic spines are the main postsynaptic elements of excitatory synapses and are crucial structures for memory and cognition. Furthermore, PSD95 has an essential function for synaptic maintenance and plasticity. PSD95 synthesis is controlled by the REST–miR124a–PTBP1 axis. Here, we report that high levels of 27-OH induce REST–miR124a–PTBP1 axis dysregulation in a possible RxRγ-dependent manner, suggesting that 27-OH reduces PSD95 levels through this mechanism. Our results reveal a possible molecular link between hypercholesterolemia and neurodegeneration. We discuss the possibility that reduction of 27-OH levels could be a useful strategy for preventing memory and cognitive decline in neurodegenerative disorders.

Serotonergic dysfunction is implicated in Alzheimer's disease (AD). In addition, reductions in brain of both monoamine synthesis and release have been reported. Serotonin 1B receptors (5-HT1B), along with serotonin transporter (SERT) are among the regulators of extracellular 5-HT levels. We investigated the effect of the familial AD APP (Amyloid precursor protein) K670N/M671L double mutation, APP Swedish mutation (APPswe), on the expression of 5-HT1B, SERT, MAOA, p11 and 5-HT and its metabolite 5-HIAA in SH-SY5Y human neuroblastoma cell line stably transfected with APPswe mutation. In addition, hippocampal expressions of 5-HT1B and SERT were assessed in wild type and transgenic mice expressing APPswe mutation (Tg2576) at different age groups. We found a reduction of 5-HT1B as well as SERT in both APPswe in vitro and ex vivo. P11 and 5HT were also reduced, whereas 5HT turnover and MAOA were increased. Our results indicate that APPswe induced decreased 5-HT1B expression and 5-HT release, as well as increased MAOA activity and 5-HT breakdown. Further studies to explore the detailed mechanism behind reduced 5-HT1B and SERT in AD and their clinical implications are needed.

In spite of the fact that cholesterol does not pass the blood-brain barrier, treatment of mice with dietary cholesterol causes significant effects on a number of genes in the brain and in addition a memory impairment. We have suggested that these effects are mediated by 27-hydroxycholesterol, which is able to pass the blood-brain barrier. To test this hypothesis we utilized Cyp27-/- mice lacking 27-hydroxycholesterol. The negative effect on memory observed after treatment of wildtype mice with dietary cholesterol was not observed in these mice. The cholesterol diet reduced the levels of the "memory protein" Arc (Activity Regulated Cytoskeleton associated protein) in the hippocampus of the wildtype mice but not in the hippocampus of the Cyp27-/- mice. The results are consistent with 27-hydroxycholesterol as the mediator of the negative effects of cholesterol on cognition.

Inflammation plays an important role in Alzheimer's disease (AD) and other neurodegenerative disorders. Although chronic inflammation in later stages of AD is well described, little is known about the inflammatory processes in preclinical or early stages of the disease prior to plaque deposition. In this study, we report that the inflammatory mediator S100A8 is increased with aging in the mouse brain. It is observed as extracellular aggregates, which do not correspond to corpora amylacea. S100A8 aggregation is enhanced in the hippocampi of two different mouse models for amyloid-β (Aβ) overproduction (Tg2576 and TgAPParctic mice). S100A8 aggregates are seen prior the formation of Aβ plaques and do not colocalize. In vitro treatment of glial cells from primary cultures with Aβ42 resulted in an increased production of S100A8. In parallel, treatment of a neuronal cell line with recombinant S100A8 protein resulted in enhanced Aβ42 and decreased Aβ40 production. Our results suggest that important inflammatory processes are occurring prior to Aβ deposition and the existence of a positive feedback between S100A8 and Aβ productions. The possible relevance of aging- or AD-dependent formation of S100A8 aggregates in the hippocampus thus affecting learning and memory processes is discussed.

The presence of the E4 allele of apolipoprotein E (apoE) is the strongest known genetic risk factor for sporadic Alzheimer's disease (AD). Other risk factors for developing AD have been identified, including lifestyle such as dietary habits. The present study was designed to explore the impact of the interaction between variant human apoE isoforms and a high carbohydrate diet (HCD) on mechanisms behind learning and memory retention. As an investigative model, we compared young apoE3 and apoE4 target replacement mice fed on a HCD for 6 months. Our results indicate that HCD compromises memory processes in apoE4 mice. ApoE4 mice on HCD showed decreased activity-regulated cytoskeletal-associated protein (Arc) and brain derived neurotrophic factor (BDNF) levels, as well as decreased BDNF signaling in the hippocampus. In contrast, apoE3 mice were resistant to the deleterious effects of HCD on both behavior and memory-related proteins. Our results support the hypothesis that already in mid-life, genetic, and environmental risk factors act together on the mechanisms behind cognitive impairment.

The perirhinal cortex (PRh) is strategically located between the neocortex and memory-related structures such as the entorhinal cortex and the hippocampal formation. The pattern of strong reciprocal connections between these areas, together with experimental evidence that PRh damage induces specific memory deficits, has placed this cortical region at the center of a growing interest for its role in learning and memory mechanisms. The aim of the present study is to clarify the involvement of PRh in learning and retention in a novel experimental model of spatial working memory, the water T-maze. The data show that pre-acquisition neurotoxic PRh lesions caused task-learning deficits. This impairment was observed during the acquisition phase as well as the retrieval phase. On the other hand, a post-acquisition PRh neurotoxic lesion failed to impair the acquisition and the retrieval of the water T-maze task performed 32 day after lesion. These results suggest a possible key role of PRh in the acquisition but not in the retention of a working memory task. Furthermore, these results show that the water T-maze may be a suitable learning paradigm to study different components of learning and memory.