AD-related Neuropathology Research Articles

Interaction of Cigarette Smoking History With APOE Genotype and Age on Amyloid Level, Glucose Metabolism, and Neurocognition in Cognitively Normal Elders.

Chronic cigarette smoking is associated with increased risk for Alzheimer's disease (AD). The goal of this study was to determine if smoking history moderated the associations of age and APOE genotype (the most robust risk factors for AD) on brain amyloid deposition, glucose metabolism, and neurocognition in cognitively-normal elders. Participants (n = 264) were grouped according to their APOE ε4 carrier status (ε4 carrier: APOE4+; non-ε4 carrier: APOE4-) and smoking status (smokers: at least 1 year of smoking during lifetime; never-smokers: no history of smoking). Approximately 89% of the smoking sample was former-smokers. We specifically tested for interactions of smoking status with APOE ε4 carrier status and age on measures of cortical amyloid deposition, glucose metabolism, and neurocognition. (1) smoking status interacted with APOE ε4 carrier status, where smoker APOE4+ showed lower glucose metabolism and poorer auditory-verbal learning and memory than never-smoking APOE4-, never-smoking APOE4+, and smoking APOE4-; (2) smoking status interacted with age on measures of semantic fluency, processing speed/set-shifting and global neurocognition; smokers, irrespective of APOE ε4 carrier status, demonstrated poorer performance with increasing age than never-smokers; and (3) smoking APOE4+ and never-smoking APOE4+ showed greater cortical amyloid deposition than never-smoking APOE4- and smoking APOE4-. The findings indicate consideration of smoking history is essential to both better understand the factors associated with neurobiological and neurocognitive abnormalities in elders, and the risk for development of AD-related neuropathology.

Regional and sub-regional differences in hippocampal GABAergic neuronal vulnerability in the TgCRND8 mouse model of Alzheimer's disease.

Hippocampal network activity is predominantly coordinated by γ-amino-butyric acid (GABA)ergic neurons. We have previously hypothesized that the altered excitability of hippocampal neurons in Alzheimer's disease (AD), which manifests as increased in vivo susceptibility to seizures in the TgCRND8 mouse model of AD, may be related to disruption of hippocampal GABAergic neurons. In agreement, our previous study in TgCRND8 mice has shown that hippocampal GABAergic neurons are more vulnerable to AD-related neuropathology than other types of neurons. To further explore the mechanisms behind the observed decrease of GABAergic neurons in 6 month-old TgCRND8 mice, we assessed the relative proportion of somatostatin (SOM), neuropeptide Y (NPY) and paravalbumin (PV) sub-types of GABAergic neurons at the regional and sub-regional level of the hippocampus. We found that NPY expressing GABAergic neurons were the most affected, as they were decreased in CA1-CA2 (pyramidal-, stratum oriens, stratum radiatum and molecular layers), CA3 (specifically in the stratum oriens) and dentate gyrus (specifically in the polymorphic layer) in TgCRND8 mice as compared to non-transgenic controls. SOM expressing GABAergic neurons were decreased in CA1-CA2 (specifically in the stratum oriens) and in the stratum radiatum of CA3, whereas PV neurons were significantly altered in stratum oriens sub-region of CA3. Taken together, these data provide new evidence for the relevance of hippocampal GABAergic neuronal network disruption as a mechanism underlying AD sequelae such as aberrant neuronal excitability, and further point to complex hippocampal regional and sub-regional variation in susceptibility to AD-related neuronal loss.

The Link Between Physical Activity and Cognitive Dysfunction in Alzheimer Disease.

Alzheimer disease (AD) is a primary cause of cognitive dysfunction in the elderly population worldwide. Despite the allocation of enormous amounts of funding and resources to studying this brain disorder, there are no effective pharmacological treatments for reducing the severity of pathology and restoring cognitive function in affected people. Recent reports on the failure of multiple clinical trials for AD have highlighted the need to diversify further the search for new therapeutic strategies for cognitive dysfunction. Thus, studies detailing the neuroprotective effects of physical activity (PA) on the brain in AD were reviewed, and mechanisms by which PA might mitigate AD-related cognitive decline were explored. A MEDLINE database search was used to generate a list of studies conducted between January 2007 and September 2014 (n=394). These studies, along with key references, were screened to identify those that assessed the effects of PA on AD-related biomarkers and cognitive function. The search was not limited on the basis of intensity, frequency, duration, or mode of activity. However, studies in which PA was combined with another intervention (eg, diet, pharmacotherapeutics, ovariectomy, cognitive training, behavioral therapy), and studies not written in English were excluded. Thirty-eight animal and human studies met entry criteria. Most of the studies suggested that PA attenuates neuropathology and positively affects cognitive function in AD. Although the literature lacked sufficient evidence to support precise PA guidelines, convergent evidence does suggest that the incorporation of regular PA into daily routines mitigates AD-related symptoms, especially when deployed earlier in the disease process. Here the protocols used to alter the progression of AD-related neuropathology and cognitive decline are highlighted, and the implications for physical therapist practice are discussed.

Modulation of AD neuropathology and memory impairments by the isoprostane F2α is mediated by the thromboxane receptor

Beside amyloid-β plaques and neurofibrillary tangles, brain oxidative damage has been constantly implicated in Alzheimer's disease (AD) pathogenesis. Numerous studies demonstrated that F2-isoprostanes, markers of in vivo lipid peroxidation, are elevated in AD patients and mouse models of the disease. Previously, we showed that the 8-isoprostaneF2α, (8ISO) increases brain amyloid-β levels and deposition in the Tg2576 mice. However, no data are available on its effects on behavior and tau metabolism. To this end, we characterize the behavioral, biochemical, and neuropathologic effects of 8ISO in the triple transgenic mouse model. Compared with controls, mice receiving 8ISO showed significant memory deficits, increase in tau phosphorylation, activation of the cyclin kinase 5 pathway, and neuroinflammation. All these effects were blocked by pharmacologic blockade of the thromboxane receptor. Our findings establish the novel functional role that oxidative stress via the formation of this isoprostane plays in the development of cognitive impairments and AD-related tau neuropathology. It provides important preclinical support to the neurobiological importance of the thromboxane receptor as an active player in the pathogenesis of AD.

Triptolide preserves cognitive function and reduces neuropathology in a mouse model of Alzheimer's disease.

Triptolide, a major bioactive ingredient of a widely used herbal medicine, has been shown to possess multiple pharmacological functions, including potential neuroprotective effects pertinent to Alzheimer's disease (AD) in vitro. However, the therapeutic potential of triptolide for AD in vivo has not been thoroughly evaluated. In the present study, we investigated the impact of peripherally administered triptolide on AD-related behavior and neuropathology in APPswe/PS1ΔE9 (APP/PS1) mice, an established model of AD. Our results showed that two-month treatment with triptolide rescued cognitive function in APP/PS1 mice. Immunohistochemical analyses indicated that triptolide treatment led to a significant decrease in amyloid-β (Aβ) deposition and neuroinflammation in treated mice. In contrast to previous findings in vitro, biochemical analyses showed that triptolide treatment did not significantly affect the production pathway of Aβ in vivo. Intriguingly, further analyses revealed that triptolide treatment upregulated the level of insulin-degrading enzyme, a major Aβ-degrading enzyme in the brain, indicating that triptolide treatment reduced Aβ pathology by enhancing the proteolytic degradation of Aβ. Our findings demonstrate that triptolide treatment ameliorates key behavioral and neuropathological changes found in AD, suggesting that triptolide may serve as a potential therapeutic agent for AD.

Upregulation of TREM2 ameliorates neuropathology and rescues spatial cognitive impairment in a transgenic mouse model of Alzheimer's disease.

Triggering receptor expressed on myeloid cells 2 (TREM2) gene is a recently identified susceptibility gene for Alzheimer's disease (AD), as its low-frequency variants increase the risk of this disease with an odds ratio similar to that of an APOE ɛ4 allele. To date, the expression and biologic functions of TREM2 under AD context remain largely unknown. Using APPswe/PS1dE9 mice, a transgenic model of AD, we showed that TREM2 was upregulated in microglia during disease progression. For the first time, we provided in vitro and in vivo evidence that this upregulation was attributed to the increased amyloid-β (Aβ)(1-42) levels in the brain. By knockdown and overexpression of TREM2 in cultured primary microglia, we revealed that TREM2 modulated microglial functions under AD context, as it facilitated Aβ(1-42) phagocytosis and inhibited Aβ(1-42)-triggered proinflammatory responses. Meanwhile, this modulation was dependent on DAP12, the adapter protein of TREM2. More importantly, overexpression of TREM2 in the brain of APPswe/PS1dE9 mice markedly ameliorated AD-related neuropathology including Aβ deposition, neuroinflammation, and neuronal and synaptic losses, which was accompanied by an improvement in spatial cognitive functions. Taken together, our data suggest that the upregulation of TREM2 serves as a compensatory response to Aβ(1-42) and subsequently protects against AD progression by modulation of microglia functions. These findings provide insights into the role of TREM2 in AD pathogenesis, and highlight TREM2 as a potential therapeutic target for this disease.

Smoking and increased Alzheimer's disease risk: A review of potential mechanisms

BackgroundCigarette smoking has been linked with both increased and decreased risk for Alzheimer's disease (AD). This is relevant for the US military because the prevalence of smoking in the military is approximately 11% higher than in civilians. MethodsA systematic review of published studies on the association between smoking and increased risk for AD and preclinical and human literature on the relationships between smoking, nicotine exposure, and AD-related neuropathology was conducted. Original data from comparisons of smoking and never-smoking cognitively normal elders on in vivo amyloid imaging are also presented. ResultsOverall, literature indicates that former/active smoking is related to a significantly increased risk for AD. Cigarette smoke/smoking is associated with AD neuropathology in preclinical models and humans. Smoking-related cerebral oxidative stress is a potential mechanism promoting AD pathology and increased risk for AD. ConclusionsA reduction in the incidence of smoking will likely reduce the future prevalence of AD.

Sex-Specific Effects of High Fat Diet on Indices of Metabolic Syndrome in 3xTg-AD Mice: Implications for Alzheimer's Disease

Multiple factors of metabolic syndrome have been implicated in the pathogenesis of Alzheimer's disease (AD), including abdominal obesity, insulin resistance, endocrine dysfunction and dyslipidemia. High fat diet, a common experimental model of obesity and metabolic syndrome, has been shown to accelerate cognitive decline and AD-related neuropathology in animal models. However, sex interacts with the metabolic outcomes of high fat diet and, therefore, may alter neuropathological consequences of dietary manipulations. This study examines the effects of sex and high fat diet on metabolic and AD-related neuropathological outcomes in 3xTg-AD mice. Three month-old male and female 3xTg-AD mice were fed either standard or high fat diets for 4 months. Obesity was observed in all high fat fed mice; however, ectopic fat accumulation, hyperglycemia and hyperinsulinemia were observed only in males. Interestingly, despite the different metabolic outcomes of high fat diet, the neuropathological consequences were similar: both male and female mice maintained under high fat diet exhibited significant worsening in behavioral performance and hippocampal accumulation of β-amyloid protein. Because high fat diet resulted in obesity and increased AD-like pathology in both sexes, these data support a role of obesity-related factors in promoting AD pathogenesis.

Improving cognition to improve gait in Alzheimer's disease: A complementary approach to reduce fall risk in the cognitively impaired

paired t test. Results: Participants randomized to NF improved statistically within 3 months in cognitive performance as ascertained by Clox-1 and the Dementia Rating Scale, and their caregivers reported improvement in Neuropsychiatric Inventory. Participants receiving NF either continued to improve or maintained their baseline performance during open-label extensions.Participants randomized to placebo did not improve, but during open-label extensions displayed similar improvement within 3 months to that of participants initially randomized to NF. Caregivers reported no change in Activities of Daily Living for either cohort. Conclusions: These findings confirm and extend prior phase I studies in which NF improved or maintained cognitive performance and behavioral symptoms for individuals with AD, and improved cognitive performance for community-dwelling individuals without dementia.Studies with transgenic mice demonstrated that supplementation with NF reduced PS-1 expression, beta and gamma secretase activity, intracellular Abeta, extracellular Abeta deposits, phospho-tau, homocysteine and oxidative damage, and increased levels of acetylcholine and glutathione. While these biochemical and histological parameters have not been investigated in clinical studies, the comprehensive impact of NF on AD-related neuropathology in preclinical findings, (in particular diminishing Abeta burden), support the possibility that consumption of NF prior to cognitive decline may delay the onset as well as progression of dementia.

A nutritional formulation for cognitive performance and mood in Alzheimer's disease and mild cognitive impairment: A phase II multisite randomized trial with an open-label extension

Background It is increasingly recognized that interventions for dementia must shift towards prevention to obtain maximal efficacy and any significant degree of disease modification. Nutritional supplementation with single agents has shown varied results, suggesting the need for combinatorial intervention. Methods We conducted a 3-month, randomized, multi-site, phase II study in which 141 individuals diagnosed with Alzheimer’s disease (AD) and 34 individuals with Mild Cognitive Impairment received a nutraceutical formulation (NF; folate, alpha-tocopherol, B12, S-adenosyl methioinine, N-acetyl cysteine, acetyl-L-carnitine) or indistinguishable placebo under double-blind conditions, followed by an open-label extension in which all individuals received NF for a total of 1yr. An additional 38 individuals with AD received NF under open-label conditions from baseline for 1yr. The primary outcome was defined as cognitive performance. Secondary outcomes were defined as behavioral and psychological symptoms of dementia and activities of daily living. Results Participants radomized to NF improved statistically within 3 months in cognitive performance as ascertained by Clox-1 and the Dementia Rating Scale, and their caregivers reported improvement in Neuropsychiatric Inventory. Participants receiving NF either continued to improve or maintained their baseline performance during open-label extensions. Participants randomized to placebo did not improve, but during open-label extensions displayed similar improvement within 3 months to that of participants initially randomized to NF. Caregivers reported no change in Activities of Daily Living for either cohort. Conclusions These findings confirm and extend prior phase I studies in which NF improved or maintained cognitive performance and behavioral symptoms for individuals with AD, and improved cognitive performance for community-dwelling individuals without dementia. In published studies with transgenic mice NF reduced PS-1 expression, beta and gamma secretase activity, Abeta deposits, phospho-tau, homocysteine and oxidative damage, and increased acetylcholine and glutathione. This comprehensive impact of NF on AD-related neuropathology supports the possibility that NF may harbor disease-modifying properties.

Ligand for Translocator Protein Reverses Pathology in a Mouse Model of Alzheimer's Disease

Ligands of the translocator protein (TSPO) elicit pleiotropic neuroprotective effects that represent emerging treatment strategies for several neurodegenerative conditions. To investigate the potential of TSPO as a therapeutic target for Alzheimer's disease (AD), the current study assessed the effects of the TSPO ligand Ro5-4864 on the development of neuropathology in 3xTgAD mice. The effects of the TSPO ligand on neurosteroidogenesis and AD-related neuropathology, including β-amyloid accumulation, gliosis, and behavioral impairment, were examined under both early intervention (7-month-old young-adult male mice with low pathology) and treatment (24-month-old, aged male mice with advanced neuropathology) conditions. Ro5-4864 treatment not only effectively attenuated development of neuropathology and behavioral impairment in young-adult mice but also reversed these indices in aged 3xTgAD mice. Reduced levels of soluble β-amyloid were also observed by the combination of TSPO ligands Ro5-4864 and PK11195 in nontransgenic mice. These findings suggest that TSPO is a promising target for the development of pleiotropic treatment strategies for the management of AD.

Alzheimer's disease pathology does not mediate the association between depressive symptoms and subsequent cognitive decline

BackgroundDepressive symptoms in nondemented individuals appear to hasten the progression from mild cognitive impairment to clinical Alzheimer's disease (AD) and double the risk of incident AD. However, the mechanism(s) by which depression might affect this risk has not been well established. The purpose of this analysis was to test the hypothesis that AD pathology mediates depression's apparent effect on the risk of dementia conversion using longitudinally collected psychometric testing and autopsy data from the Honolulu–Asia Aging Study. MethodsLatent factor variables representing AD, cortical Lewy body (CLB), and ischemic neuropathology were tested as potential mediators of the association between the Center for Epidemiological Studies depression scale (CES-D) score and the 10-year prospective rate of cognitive decline, adjusted for baseline cognition, age, education, total number of medications, and brain weight at autopsy. ResultsCES-D scores, neurofibrillary tangle counts, CLB counts, and ischemic lesions each made significant independent contributions to cognitive decline. However, CES-D scores were not significantly associated with any pathological variable; thus the pathological variables were not mediators of the effect of CES-D scores on cognitive decline. ConclusionsSubsyndromal depressive symptoms are significantly associated with subsequent cognitive decline. Although the effect is relatively modest, it is stronger than that of amyloid-related neuropathologies and independent of that of neurofibrillary tangles, cortical Lewy bodies, and ischemic lesions. Our results argue against the role of AD-related neuropathology as a mediator of depression's effect on cognitive decline, but cannot rule out a significant mediation effect in a subset of cases, perhaps with more severe baseline depressive symptoms.

Latrepirdine improves cognition and arrests progression of neuropathology in an Alzheimer's mouse model

Latrepirdine (Dimebon) is a pro-neurogenic, antihistaminic compound that has yielded mixed results in clinical trials of mild to moderate Alzheimer's disease, with a dramatically positive outcome in a Russian clinical trial that was unconfirmed in a replication trial in the United States. We sought to determine whether latrepirdine (LAT)-stimulated amyloid precursor protein (APP) catabolism is at least partially attributable to regulation of macroautophagy, a highly conserved protein catabolism pathway that is known to be impaired in brains of patients with Alzheimer's disease (AD). We utilized several mammalian cellular models to determine whether LAT regulates mammalian target of rapamycin (mTOR) and Atg5-dependent autophagy. Male TgCRND8 mice were chronically administered LAT prior to behavior analysis in the cued and contextual fear conditioning paradigm, as well as immunohistological and biochemical analysis of AD-related neuropathology. Treatment of cultured mammalian cells with LAT led to enhanced mTOR- and Atg5-dependent autophagy. Latrepirdine treatment of TgCRND8 transgenic mice was associated with improved learning behavior and with a reduction in accumulation of Aβ42 and α-synuclein. We conclude that LAT possesses pro-autophagic properties in addition to the previously reported pro-neurogenic properties, both of which are potentially relevant to the treatment and/or prevention of neurodegenerative diseases. We suggest that elucidation of the molecular mechanism(s) underlying LAT effects on neurogenesis, autophagy and behavior might warranty the further study of LAT as a potentially viable lead compound that might yield more consistent clinical benefit following the optimization of its pro-neurogenic, pro-autophagic and/or pro-cognitive activities.

Pharmacological prevention and treatment of vascular dementia: Approaches and perspectives

Vascular dementia (VaD) is a common dementing illness. There are no pharmacological agents with a regulatory approval for its treatment or prevention. Review of published clinical trial reports indicates that early treatment of hypertension, a risk factor for stroke, reduces VaD risk and slows progression. However, unlike stroke, treatment of hyperlipidemia with statin class drugs or treatment of blood clotting abnormalities with acetylsalicylic acid do not appear to have an effect on VaD incidence or progression. Pharmacological agents for treatment of Alzheimer's dementia (AD) such as memantine or acetylcholinesterase inhibitors have small positive effects on cognition in VaD, which are likely due to their action on co-existing AD-related neuropathology. Drug development efforts using novel approaches such as patient stratification by their genotype are needed in order to address the increasing need for effective VaD therapeutics.

Behavioral and neurobiological effects of prenatal stress exposure in male and female APPswe/PS1dE9 mice

Epidemiological evidence implies a role for chronic stress and stress-related disorders in the etiopathogenesis of sporadic Alzheimer's disease (AD). Although chronic stress exposure during various stages of life has been shown to exacerbate AD-related cognitive deficits and neuropathology in AD mouse models, the role of stress exposure during the prenatal period on AD development and progression remained to be investigated. The present study therefore explored the effects of prenatal maternal stress (PMS) in both male and female APPswe/PS1dE9 mouse offspring in terms of cognition, affect, and AD-related neuropathology. As prenatal perturbations are likely to mediate their effects via alterations in epigenetic regulation, changes in hippocampal DNA methyltransferase 3a, 5-methylcytosine and 5-hydroxymethylcytosine levels were assessed as underlying mechanisms. Repetitive restraint stress during the first week of gestation exerted a sex-dependent effect, with male PMS mice showing spatial memory deficits and a blunted hypothalamus-pituitary-adrenal axis response, while female PMS mice showed improved spatial memory performance, increased depressive-like behavior, as well as a decrease in hippocampal plaque load. In addition, sex differences were observed among APPswe/PS1dE9 mice, independent of PMS (i.e., female mice showed impaired spatial memory performance, higher hippocampal plaque load, altered amyloid precursor protein processing in the CA3 and lower DNA methyltransferase 3a immunoreactivity in the dentate gyrus when compared with male mice of the same age). In conclusion, PMS exposure impacts on the behavioral phenotype and neuropathology of APPswe/PS1dE9 mice. Moreover, given the remarkable sex differences observed, one should not overlook the impact of sex-specific responses to environmental exposures when investigating gene-environment interactions in AD.

Evidence that Ingested Aluminum Additives Contained in Processed Foods and Alum-Treated Drinking Water are a Major Risk Factor for Alzheimers Disease

Aluminum (Al) is a recognized neurotoxin causally linked to several neurodegenerative diseases with a dementia component. Al has long had a GRAS (Generally Recognized As Safe) rating by the US FDA, that allows Al salts to be used in food manufacture and clarification of urban drinking water supplies. Routine ingestion of Al salts throughout life causes bioavailable Al to accumulate in the brain where it specifically deposits in regions most vulnerable in Alzheimers disease (AD). AD has an insidious onset, developing slowly and progressively, producing cognitive deterioration in old age. The main source of Al exposure for humans is their total dietary Al intake from foods, water, other beverages, and Al additives. Prospective data collection from epidemiological studies attempting to quantify total dietary Al intake, to probe for AD causality, is virtually impossible to obtain in a human population where all its members are routinely exposed to abundant Al amounts from many sources. Longitudinal animal studies provide a parallel in that their feed and water intakes can be rigorously controlled throughout the life span. Such a study revealed that a significant proportion of rats, particularly those that consumed Al in an equivalent amount to the high end of the human total dietary Al range, progressively accumulated Al in their brain, accompanied by AD-related neuropathology and cognitive deterioration in old age. This article describes evidence for the close involvement of Al with the major AD hallmarks and provides suggestions that may help to remediate the current AD epidemic in westernized countries.

A coding variant in CR1 interacts with APOE-ɛ4 to influence cognitive decline

Complement receptor 1 (CR1) is an Alzheimer's disease (AD) susceptibility locus that also influences AD-related traits such as episodic memory decline and neuritic amyloid plaque deposition. We implemented a functional fine-mapping approach, leveraging intermediate phenotypes to identify functional variant(s) within the CR1 locus. Using 1709 subjects (697 deceased) from the Religious Orders Study and the Rush Memory and Aging Project, we tested 41 single-nucleotide polymorphisms (SNPs) within the linkage disequilibrium block containing the published CR1 AD SNP (rs6656401) for associations with episodic memory decline, and then examined the functional consequences of the top result. We report that a coding variant in the LHR-D (long homologous repeat D) region of the CR1 gene, rs4844609 (Ser1610Thr, minor allele frequency = 0.02), is associated with episodic memory decline and accounts for the known effect of the index SNP rs6656401 (D' = 1, r(2)= 0.084) on this trait. Further, we demonstrate that the coding variant's effect is largely dependent on an interaction with APOE-ε4 and mediated by an increased burden of AD-related neuropathology. Finally, in our data, this coding variant is also associated with AD susceptibility (joint odds ratio = 1.4). Taken together, our analyses identify a CR1 coding variant that influences episodic memory decline; it is a variant known to alter the conformation of CR1 and points to LHR-D as the functional domain within the CR1 protein that mediates the effect on memory decline. We thus implicate C1q and MBL, which bind to LHR-D, as likely targets of the variant's effect and suggest that CR1 may be an important intermediate in the clearance of Aβ42 particles by C1q.

Age-related changes in core body temperature and activity in triple-transgenic Alzheimer’s disease (3xTgAD) mice

SUMMARYAlzheimer’s disease (AD) is characterised, not only by cognitive deficits and neuropathological changes, but also by several non-cognitive behavioural symptoms that can lead to a poorer quality of life. Circadian disturbances in core body temperature and physical activity are reported in AD patients, although the cause and consequences of these changes are unknown. We therefore characterised circadian patterns of body temperature and activity in male triple transgenic AD mice (3xTgAD) and non-transgenic (Non-Tg) control mice by remote radiotelemetry. At 4 months of age, daily temperature rhythms were phase advanced and by 6 months of age an increase in mean core body temperature and amplitude of temperature rhythms were observed in 3xTgAD mice. No differences in daily activity rhythms were seen in 4- to 9-month-old 3xTgAD mice, but by 10 months of age an increase in mean daily activity and the amplitude of activity profiles for 3xTgAD mice were detected. At all ages (4–10 months), 3xTgAD mice exhibited greater food intake compared with Non-Tg mice. The changes in temperature did not appear to be solely due to increased food intake and were not cyclooxygenase dependent because the temperature rise was not abolished by chronic ibuprofen treatment. No β-amyloid (Aβ) plaques or neurofibrillary tangles were noted in the hypothalamus of 3xTgAD mice, a key area involved in temperature regulation, although these pathological features were observed in the hippocampus and amygdala of 3xTgAD mice from 10 months of age. These data demonstrate age-dependent changes in core body temperature and activity in 3xTgAD mice that are present before significant AD-related neuropathology and are analogous to those observed in AD patients. The 3xTgAD mouse might therefore be an appropriate model for studying the underlying mechanisms involved in non-cognitive behavioural changes in AD.

Grape Seed Polyphenolic Extract Specifically Decreases Aβ*56 in the Brains of Tg2576 Mice

Amyloid-β (Aβ) oligomers, found in the brains of Alzheimer's disease (AD) patients and transgenic mouse models of AD, cause synaptotoxicity and memory impairment. Grape seed polyphenolic extract (GSPE) inhibits Aβ oligomerization in vitro and attenuates cognitive impairment and AD-related neuropathology in the brains of transgenic mice. In the current study, GSPE was administered to Tg2576 mice for a period of five months. Treatment significantly decreased brain levels of Aβ*56, a 56-kDa Aβ oligomer previously shown to induce memory dysfunction in rodents, without changing the levels of transgenic amyloid-β protein precursor, monomeric Aβ, or other Aβ oligomers. These results thus provide the first demonstration that a safe and affordable intervention can lower the levels of a memory-impairing Aβ oligomer in vivo and strongly suggest that GSPE should be further tested as a potential prevention and/or therapy for AD.

Increased Hippocampal Default Mode Synchronization during Rest in Middle-Aged and Elderly APOE ε4 Carriers: Relationships with Memory Performance

The apolipoprotein (APOE) ε4 allele is a strong genetic risk factor for Alzheimer's disease (AD). Intrinsic fluctuations of brain activity measured by fMRI during rest may be sensitive to AD-related neuropathology. In particular, functional connectivity of the default-mode network (DMN) has gained recent attention as a possible biomarker of disease processes and associated memory decline in AD. Here, we tested the hypothesis of APOE-related alterations in DMN functional connectivity in 95 healthy individuals between 50 and 80 years of age, including 33 carriers of the ε4 allele. Based on previous studies, we hypothesized increased hippocampal DMN synchronization in APOE ε4 carriers. This was supported using independent component analysis in combination with a dual-regression approach for analysis of resting state data. Whole-brain analysis suggested effects also in other areas, including the posterior cingulate cortex, parietal cortex, and parahippocampal regions. DMN synchronization showed a negative correlation with performance on a test of memory functioning, suggesting a neurocognitive significance of the brain activity patterns during rest. Our findings indicate that increased genetic vulnerability for AD is reflected in increased hippocampal DMN synchronization during rest several years before clinical manifestation. We propose that the results reflect ε4-related failure in hippocampal decoupling, which might elevate the total hippocampal metabolic burden and increase the risk of cognitive decline and AD. The results provide an important confirmation of specific genotype effects on intrinsic fluctuations and support the use of functional connectivity indices as imaging-derived endophenotypes in the emerging field of imaging genetics.