Morphology of physiologically identified otolith-related vestibular neurons in cats

Presenilin-1 (PS1) is intimately involved in cleavage of amyloid precursor protein to form beta-amyloid peptides, certain forms of which aggregate in the brains of patients with Alzheimer's disease (AD). The function(s) of PS1 and its precise involvement in the development of cognitive deficits associated with AD are unclear. We have utilised genetically modified mice that under-express PS1 (PS1(+/-) mice) to investigate the role of PS1 in hippocampal synaptic plasticity. Field excitatory postsynaptic responses elicited by baseline stimulation were indistinguishable between PS1(+/-) mice and wild-type controls. Likewise, a measure of short-term plasticity, paired-pulse facilitation, was normal in PS1(+/-) mice. However, long-term potentiation induced by multiple tetanus trains was reduced in PS1(+/-) animals. These results demonstrate that chronic reduction of PS1 activity leads to impaired synaptic plasticity, thus suggesting a role for PS1 in normal cognitive function.     

Tauroursodeoxycholic acid suppresses amyloid β-induced synaptic toxicity in vitro and in APP/PS1 mice

Synapses are considered the earliest site of Alzheimer's disease (AD) pathology, where synapse density is reduced, and synaptic loss is highly correlated with cognitive impairment. Tauroursodeoxycholic acid (TUDCA) has been shown to be neuroprotective in several models of AD, including neuronal exposure to amyloid β (Aβ) and amyloid precursor protein (APP)/presenilin 1 (PS1) double-transgenic mice. Here, we show that TUDCA modulates synaptic deficits induced by Aβ in vitro. Specifically, TUDCA reduced the downregulation of the postsynaptic marker postsynaptic density-95 (PSD-95) and the decrease in spontaneous miniature excitatory postsynaptic currents (mEPSCs) frequency, while increasing the number of dendritic spines. This contributed to the induction of more robust and synaptically efficient neurons, reflected in inhibition of neuronal death. In vivo, TUDCA treatment of APP/PS1 mice abrogated the decrease in PSD-95 reactivity in the hippocampus. Taken together, these results expand the neuroprotective role of TUDCA to a synaptic level, further supporting the use of this molecule as a potential therapeutic strategy for the prevention and treatment of AD.     

Plasma rich in growth factors (PRGF-Endoret) reduces neuropathologic hallmarks and improves cognitive functions in an Alzheimer's disease mouse model

Impaired growth factor function is thought to drive many of the alterations observed in Alzheimer's disease (AD) patients. Endogenous regenerative technology, PRGF (plasma rich in growth factor)-Endoret, is designed for the delivery of a complex pool of patient's own active morphogens that may stimulate tissue regeneration. We obtained and characterized PRGF-Endoret preparations from human blood. We used, as experimental approach in vivo, APP/PS1 mice, characterized by age-dependent brain amyloid-β (Aβ) accumulation. Intranasal administration of PRGF-Endoret to APP/PS1 mice resulted in an important decrease in brain Aβ deposition and tau phosphorylation. PRGF-Endoret-treated APP/PS1 mice also showed decreased astrocyte reactivity, and prevented protein synaptic loss. In vitro approaches demonstrated that PRGF-Endoret treatment modulated astrocyte activation, reducing inflammatory responses, and promoted Aβ degradation. Furthermore, PRGF-Endoret stimulated global improvements in anxiety, learning, and memory behaviors. Our findings show that PRGF-Endoret exerts multifunctional and complementary effects that result in the reversal of the broad range of cognitive deficits in AD, suggesting that PRGF-Endoret may hold promise as an innovative therapy in AD.     

Xanthoceraside modulates neurogenesis to ameliorate cognitive impairment in APP/PS1 transgenic mice

Neuronal loss is reported to be an important pathological process in Alzheimer’s disease (AD). Neurogenesis is a process of generation of new neurons to fill the neuronal loss. Xanthoceraside has been shown to attenuate the cognitive deficits in several AD animal models. However, little is known about the effect of xanthoceraside on neurogenesis in APP/PS1 transgenic mice. Thus, in this study, we investigated whether xanthoceraside can ameliorate learning and memory impairment by promoting NSCs proliferation and neuronal differentiation. The results suggested that xanthoceraside significantly ameliorated the cognitive impairment and induced NSCs proliferation and neuronal differentiation in APP/PS1 transgenic mice. Meanwhile, in vitro study revealed that xanthoceraside increased the size of NSCs and induced NSCs differentiation into neurons compared with amyloid beta-peptide (25–35) (Aβ_25–35) treatment. Furthermore, we found that xanthoceraside significantly increased the expression of Wnt3a and p-GSK3β, decreased the expression of p-β-catenin, and induced nuclear translocation of β-catenin in APP/PS1 transgenic mice. Furthermore, in vitro study found that the effect of xanthoceraside on inducing NSCs proliferation and neuronal differentiation were inhibited by Wnt pathway inhibitor Dickkopf-1 (Dkk-1). Our data demonstrated that xanthoceraside may promote the proliferation and differentiation of NSCs into neurons by up-regulating the Wnt/β-catenin pathway to fill the neuronal loss, thereby improving learning and memory impairment in APP/PS1 transgenic mice.     

Locus coeruleus degeneration exacerbates olfactory deficits in APP/PS1 transgenic mice

Neuronal loss in the locus coeruleus (LC) is 1 of the early pathological events in Alzheimer's disease (AD). Projections of noradrenergic neurons of the LC innervate the olfactory bulb (OB). Because olfactory deficits have been reported in early AD, we investigated the effect of induced LC degeneration on olfactory memory and discrimination in an AD mouse model. LC degeneration was induced by treating APP/PS1 mice with N-(2-chloroethyl)-N-ethyl-bromo-benzylamine (DSP4) repeatedly between 3 and 12 months of age. Short term odor retention, ability for spontaneous habituation to an odor, and spontaneous odor discrimination were assessed by behavioral tests. DSP4 treatment in APP/PS1 mice resulted in an exacerbation of short term olfactory memory deficits and more discrete weakening of olfactory discrimination abilities, suggesting that LC degeneration contributes to olfactory deficits observed in AD. Importantly, DSP4 treatment also increased amyloid β (Aβ) deposition in the olfactory bulb of APP/PS1 mice, which correlated with olfactory memory, not with discrimination deficits.     

Neuropep-1 ameliorates learning and memory deficits in an Alzheimer's disease mouse model,increases brain-derived neurotrophic factor expression in the brain,and causes reduction of amyloid beta plaques

Alzheimer's disease (AD) is a neurodegenerative disease characterized by amyloid beta (Aβ) deposits, hyperphosphorylated tau deposition, and cognitive dysfunction. Abnormalities in the expression of brain-derived neurotrophic factor (BDNF), which plays an important role in learning and memory formation, have been reported in the brains of AD patients. A BDNF modulating peptide (Neuropep-1) was previously identified by positional-scanning synthetic peptide combinatorial library. Here we examine the neuroprotective effects of Neuropep-1 on several in vitro neurotoxic insults, and triple-transgenic AD mouse model (3xTg-AD). Neuropep-1 protects cultured neurons against oligomeric Aβ_1–42, 1-methyl-4-phenylpyridinium, and glutamate-induced neuronal cell death. Neuropep-1 injection also significantly rescues the spatial learning and memory deficits of 3xTg-AD mice compared with vehicle-treated control group. Neuropep-1 treatment markedly increases hippocampal and cortical BDNF levels. Furthermore, we found that Neuropep-1-injected 3xTg-AD mice exhibit dramatically reduced Aβ plaque deposition and Aβ levels without affecting tau pathology. Neuropep-1 treatment does not alter the expression or activity of full-length amyloid precursor protein, α-, β-, or γ-secretase, but levels of insulin degrading enzyme, an Aβ degrading enzyme, were increased. These findings suggest Neuropep-1 may be a therapeutic candidate for the treatment of AD.     

Carvedilol as a potential novel agent for the treatment of Alzheimer's disease

Oligomeric β-amyloid (Aβ) has recently been linked to synaptic plasticity deficits, which play a major role in progressive cognitive decline in Alzheimer's disease (AD). Here we present evidence that chronic oral administration of carvedilol, a nonselective β-adrenergic receptor blocker, significantly attenuates brain oligomeric β-amyloid content and cognitive deterioration in 2 independent AD mouse models. We found that carvedilol treatment significantly improved neuronal transmission, and that this improvement was associated with the maintenance of number of the less stable “learning” thin spines in the brains of AD mice. Our novel observation that carvedilol interferes with the neuropathologic, biochemical, and electrophysiological mechanisms underlying cognitive deterioration in AD supports the potential development of carvedilol as a treatment for AD.     

Acquisition of conditioned taste aversion is impaired in the amyloid precursor protein/presenilin 1 mouse model of Alzheimer's disease

Research into the underlying mechanisms of cognitive dysfunction in Alzheimer's disease (AD) has relied traditionally on tasks such as the water maze which evaluate spatial learning and memory. Since non-spatial forms of memory are also disrupted by AD, it is critical to establish other paradigms capable of investigating these deficits. Utilizing a non-spatial learning task, acquisition of conditioned taste aversion (CTA) was evaluated in a mouse model of AD. This line of transgenic mice encode a mutated allele of the human amyloid precursor protein (APP) and presenilin 1 (PS1) genes and exhibit extensive amyloid plaque deposition in the brain by 6-7 mo of age. Compared with wild-type mice, 10-17 month old APP/PS1 mice failed to acquire CTA to saccharin. Mice that only possessed one of the two mutations were able to acquire CTA to the saccharin. In 2-5 month old APP/PS1 mice acquisition of CTA was disrupted despite the lack of extensive plaque deposition. However, further analysis indicated a potential gender difference in both the CTA deficit and onset of plaque deposition with females showing greater conditioned aversion.     

Quantitative MRI reveals aging-associated T2 changes in mouse models of Alzheimer's disease

In this study, we used MRI to analyze quantitative parametric maps of transverse (T(2)) relaxation times in a longitudinal study of transgenic mice expressing mutant forms of amyloid precursor protein (APP), presenilin (PS1), or both (PS/APP), modeling aspects of Alzheimer's disease (AD). The main goal was to characterize the effects of progressive beta-amyloid accumulation and deposition on the biophysical environment of water and to investigate if these measurements would provide early indirect evidence of AD pathological changes in the brains of these mice. Our results demonstrate that at an early age before beta-amyloid deposition, only PS/APP mice show a reduced T(2) in the hippocampus and cortex compared with wild-type non-transgenic (NTg) controls, whereas a statistically significant within-group aging-associated decrease in T(2) values is seen in the cortex and hippocampus of all three transgenic genotypes (APP, PS/APP, and PS) but not in the NTg controls. In addition, for animals older than 12 months, we confirmed our previous report that only the two genotypes that form amyloid plaques (APP and PS/APP) have significantly reduced T(2) values compared with NTg controls. Thus, T(2) changes in these AD models can precede amyloid deposition or even occur in AD models that do not deposit beta-amyloid (PS mice), but are intensified in the presence of amyloid deposition.     

PET imaging with [18F]AV-45 in an APP/PS1-21 murine model of amyloid plaque deposition

Alzheimer's disease (AD), the most common age-related neurodegenerative disorder, is characterized by the accumulation of β-amyloid peptide. In man, [18F]AV-45 with positron emission tomography (PET) is currently studied and used to track in vivo amyloid accumulation. Here, [18F]-AV45-PET was used to visualize amyloid deposition in a transgenic murine model of amyloidosis (APP/PS1-21). Studies were performed ex vivo by autoradiography and in vivo by microPET. Autoradiograms of the brain sections highlighted an increased uptake of [18F]AV-45 in APP/PS1-21 mice compared with age-matched control mice. From 8 months, an intense labeling was observed in cortex, hippocampus, and striatum. The marked accumulation of radiotracer was found in close association with thioflavin S-positive amyloid plaques. The longitudinal microPET assessment, performed from 3 to 12 months of age, demonstrated an increased [18F]AV-45 uptake in APP/PS1-21 compared with control mice. The elevated tracer uptake was increased in association with age. This study opens the possibility of [18F]AV-45, coupled with microPET, to visualize and quantitatively measure amyloid deposits in the brains of living APP/PS1 mice.     

Berberine ameliorates β-amyloid pathology, gliosis, and cognitive impairment in an Alzheimer's disease transgenic mouse model

The accumulation of β-amyloid (Aβ) peptide derived from abnormal processing of amyloid precursor protein (APP) is a common pathological hallmark of Alzheimer's disease (AD) brains. In this study, we evaluated the therapeutic effect of berberine (BBR) extracted from Coptis chinensis Franch, a Chinese medicinal herb, on the neuropathology and cognitive impairment in TgCRND8 mice, a well established transgenic mouse model of AD. Two-month-old TgCRND8 mice received a low (25 mg/kg per day) or a high dose of BBR (100 mg/kg per day) by oral gavage until 6 months old. BBR treatment significantly ameliorated learning deficits, long-term spatial memory retention, as well as plaque load compared with vehicle control treatment. In addition, enzyme-linked immunosorbent assay (ELISA) measurement showed that there was a profound reduction in levels of detergent-soluble and -insoluble β-amyloid in brain homogenates of BBR-treated mice. Glycogen synthase kinase (GSK)3, a major kinase involved in APP and tau phosphorylation, was significantly inhibited by BBR treatment. We also found that BBR significantly decreased the levels of C-terminal fragments of APP and the hyperphosphorylation of APP and tau via the Akt/glycogen synthase kinase 3 signaling pathway in N2a mouse neuroblastoma cells stably expressing human Swedish mutant APP695 (N2a-SwedAPP). Our results suggest that BBR provides neuroprotective effects in TgCRND8 mice through regulating APP processing and that further investigation of the BBR for therapeutic use in treating AD is warranted.     

Cannabinoid receptor 1 deficiency in a mouse model of Alzheimer's disease leads to enhanced cognitive impairment despite of a reduction in amyloid deposition

Alzheimer's disease (AD) is characterized by amyloid-β deposition in amyloid plaques, neurofibrillary tangles, inflammation, neuronal loss, and cognitive deficits. Cannabinoids display neuromodulatory and neuroprotective effects and affect memory acquisition. Here, we studied the impact of cannabinoid receptor type 1 (CB1) deficiency on the development of AD pathology by breeding amyloid precursor protein (APP) Swedish mutant mice (APP23), an AD animal model, with CB1-deficient mice. In addition to the lower body weight of APP23/CB1^−/− mice, most of these mice died at an age before typical AD-associated changes become apparent. The surviving mice showed a reduced amount of APP and its fragments suggesting a regulatory influence of CB1 on APP processing, which was confirmed by modulating CB1 expression in vitro. Reduced APP levels were accompanied by a reduced plaque load and less inflammation in APP23/CB1^−/− mice. Nevertheless, compared to APP23 mice with an intact CB1, APP23/CB1^−/− mice showed impaired learning and memory deficits. These data argue against a direct correlation of amyloid plaque load with cognitive abilities in this AD mouse model lacking CB1. Furthermore, the findings indicate that CB1 deficiency can worsen AD-related cognitive deficits and support a potential role of CB1 as a pharmacologic target.     

Iron overload accelerates neuronal amyloid-β production and cognitive impairment in transgenic mice model of Alzheimer's disease

Iron dyshomeostasis is proving increasingly likely to be involved in the pathology of Alzheimer's disease (AD); yet, its mechanism is not well understood. Here, we investigated the AD-related mechanism(s) of iron-sulfate exposure in vitro and in vivo, using cultured primary cortical neurons and APP/PS1 AD-model mice, respectively. In both systems, we observed iron-induced disruptions of amyloid precursor protein (APP) processing, neuronal signaling, and cognitive behavior. Iron overload increased production of amyloidogenic KPI-APP and amyloid beta. Further, this APP misprocessing was blocked by MK-801 in vitro, suggesting the effect was N-methyl-d-aspartate receptor (NMDAR) dependent. Calcium imaging confirmed that 24 hours iron exposure led to disrupted synaptic signaling by augmenting GluN2B-containing NMDAR expression–GluN2B messenger RNA and protein levels were increased and promoting excessing extrasynaptic NMDAR signaling. The disrupted GluN2B expression was concurrent with diminished expression of the splicing factors, sc35 and hnRNPA1. In APP/PS1 mice, chronic iron treatment led to hastened progression of cognitive impairment with the novel object recognition discrimination index, revealing a deficit at the age of 4 months, concomitant with augmented GluN2B expression. Together, these data suggest iron-induced APP misprocessing and hastened cognitive decline occur through inordinate extrasynaptic NMDAR activation.     

Human umbilical cord blood-derived mesenchymal stem cells improve neuropathology and cognitive impairment in an Alzheimer's disease mouse model through modulation of neuroinflammation

Human umbilical cord blood-derived mesenchymal stem cells (hUCB-MSC) have a potential therapeutic role in the treatment of neurological disorders, but their current clinical usage and mechanism of action has yet to be ascertained in Alzheimer's disease (AD). Here we report that hUCB-MSC transplantation into amyloid precursor protein (APP) and presenilin1 (PS1) double-transgenic mice significantly improved spatial learning and memory decline. Furthermore, amyloid-β peptide (Aβ) deposition, β-secretase 1 (BACE-1) levels, and tau hyperphosphorylation were dramatically reduced in hUCB-MSC transplanted APP/PS1 mice. Interestingly, these effects were associated with reversal of disease-associated microglial neuroinflammation, as evidenced by decreased microglia-induced proinflammatory cytokines, elevated alternatively activated microglia, and increased anti-inflammatory cytokines. These findings lead us to suggest that hUCB-MSC produced their sustained neuroprotective effect by inducing a feed-forward loop involving alternative activation of microglial neuroinflammation, thereby ameliorating disease pathophysiology and reversing the cognitive decline associated with Aβ deposition in AD mice.     

Effects of mild chronic cerebral hypoperfusion and early amyloid pathology on spatial learning and the cellular innate immune response in mice

Understanding the contribution of cerebrovascular factors in the progression of cognitive decline in Alzheimer's disease (AD) is a key step for the development of preventive therapies. Among these factors, chronic cerebral hypoperfusion is an early component of AD pathogenesis that can predict the progression from mild cognitive impairment to AD. Here, we investigated the effects of a protocol of mild chronic cerebral hypoperfusion in the APPswe/PS1 transgenic mouse model of AD. We observed that the permanent occlusion of the right common carotid artery induced spatial learning impairments in young APPswe/PS1 mice, but not in their wild type littermates. Furthermore, the extent of learning deficits strongly correlated with the number of cortical β-amyloid plaques, with the mobilization of monocytes into the blood and with the number of bone marrow-derived microglia in the brain. These results indicate that a mild reduction of cerebral blood flow can selectively induce cognitive deficits at an early stage of amyloid pathology, eliciting a cellular innate immune response, even without causing neuronal death.     

Deep cervical lymph node ligation aggravates AD‐like pathology of APP/PS1 mice

The imbalance between production and clearance of amyloid‐beta (Aβ) is a key step in the onset and development of Alzheimer’s disease (AD). Therefore, reducing Aβ accumulation in the brain is a promising therapeutic strategy for AD. The recently discovered glymphatic system and meningeal lymphatic vasculature have been shown to be critical for the elimination of interstitial waste products, especially Aβ, from the brain. In the present study, ligation of deep cervical lymph nodes was performed to block drainage of this system and explore the consequences on Aβ‐related pathophysiology. Five‐month‐old APP/PS1 mice and their wild‐type littermates received deep cervical lymphatic node ligation. One month later, behavioral testing and pathological analysis were conducted. Results demonstrated that ligation of dcLNs exacerbated AD‐like phenotypes of APP/PS1 mice, showing more severe brain Aβ accumulation, neuroinflammation, synaptic protein loss, impaired polarization of aquaporin‐4 and deficits in cognitive and exploratory behaviors. These results suggest that brain lymphatic clearance malfunction is one of the deteriorating factors in the progression of AD, and restoring its function is a potential therapeutic target against AD.     

Early development of social deficits in APP and APP-PS1 mice

Mimicking relevant behavioral features of the human pathology is one of the most important challenges for animal models of neurological disorders including Alzheimer disease (AD). Indeed, the most popular genetic AD mouse lines bearing mutations of the amyloid precursor protein (APP) and presenilin 1 genes (PS1), often fail to present robust cognitive deficits or show them only at very advanced ages. It is therefore crucial to identify AD-like behavioral alterations which may reliably reflect the early stages of the pathology, thus permitting tests of more efficient early therapeutic interventions. Here, we demonstrated the very early expression of noncognitive AD-like symptoms, i.e., deficits in social interest, interaction and communication, in APP and APP-PS1 transgenic mice. Conversely, other noncognitive behaviors (sensori-motor gating) as well as cognitive abilities (spontaneous alternation) were unaltered in AD transgenics. Our data suggest that social deficits precede other neuropsychiatric and cognitive AD-like symptoms and can be employed as early markers of AD pathology in genetic mouse models.     

The alpha7 nicotinic receptor agonist 4OH-GTS-21 protects axotomized septohippocampal cholinergic neurons in wild type but not amyloid-overexpressing transgenic mice

While activation of alpha7 nicotinic receptors protects neurons from a variety of apoptotic insults in vitro, little is known about this neuroprotective action in vivo, especially under amyloidogenic conditions that mimic Alzheimer's disease. We therefore investigated the effects of 4OH-GTS-21, a selective partial agonist for these receptors, on septohippocampal cholinergic and GABAergic neuron survival following fimbria fornix (FFX) lesions in three strains of mice: C57BL/6J wild type mice; human presenilin-1 mutant M146L (PS1) transgenic mice; and mice expressing both mutant PS1 and Swedish mutant K670N/M671L amyloid precursor protein (APP). Initial studies to demonstrated that 4OH-GTS-21 is likely brain permeant based on its ability to improve passive avoidance and Morris water task behaviors in nucleus basalis-lesioned rats. In FFX-lesioned mice, twice per day i.p. injections of 1 mg/kg of 4OH-GTS-21 for 2 weeks promoted the survival and prevented the atrophy of septal cholinergic neurons. Septal parvalbumin-staining GABAergic neurons were not protected by this treatment, although they also express alpha7 nicotinic receptors, suggesting an indirect, nerve growth factor (NGF)-mediated mechanism. No protection of cholinergic neurons was observed in similarly treated PS1 or APP/PS1 transgenic mice. 4OH-GTS-21 treatment actually reduced cholinergic neuronal size in APP/PS1 mice. Hippocampal amyloid deposition was not affected by FFX lesions or treatment with this alpha7 nicotinic receptor agonist in APP/PS1 mice under these conditions. These results indicate that brain alpha7 nicotinic receptors are potential targets for protecting at-risk brain neurons in Alzheimer's disease, perhaps via their effects on NGF receptors; however, this protection may be sensitive under some conditions to environmental factors such as inhibitory amyloid-peptides.     

A combination extract of ginseng, epimedium, polygala, and tuber curcumae increases synaptophysin expression in APPV717I transgenic mice

ABSTRACT: BACKGROUND: The density of presynaptic markers of synaptic communication and plasticity, especially synaptophysin (SYP), is significantly correlated with cognitive decline and the progression of Alzheimer's disease (AD), indicating that synaptic protection is an important therapeutic strategy for AD. This study aims to investigate the synaptic protective effects of a combination of several active components extracted from the Chinese herbs ginseng, epimedium, polygala and tuber curcumae (GEPT), in the brains of APPV717I transgenic mice. METHODS: Three-month-old APPV717I mice were arbitrarily divided into 10 groups (n = 12 per group): APP groups receiving vehicle treatment for four or eight months (model groups), three dose groups of GEPT-treated mice for each treatment period, and donepezil-treated mice for each treatment period. Three-month-old C57BL/6J mice (n = 12) were also given vehicle for four or eight months (control groups). Vehicle, donepezil or GEPT were intragastrically administered. Immunohistochemistry (IHC) and Western blot analysis were used to assess protein expression in the hippocampal CA1 region and ratios of SYP to beta-actin levels in hippocampal tissue homogenate, respectively. RESULTS: Both IHC and Western blot revealed a decrease in SYP levels in the CA1 region of 7- and 11-month-old APPV717I transgenic mice compared with the control groups, whereas SYP levels were increased in donepezil- and GEPT-treated transgenic mice compared with the APP group. There was a significant difference in the levels of SYP detected by IHC between the GEPT high-dose group and the APP group after 4 months of treatment, and there were significant differences between all three GEPT groups and the APP group after 8 months of treatment. Western blotting showed that the SYP protein-beta-actin ratio was decreased in APP mice, while donepezil- and GEPT-treated transgenic mice showed increased trends in the SYP protein-beta-actin ratios. CONCLUSION: GEPT increases SYP expression and protects synapses before and after the formation of amyloid plaques in the brains of APPV717I transgenic mice.     

Caloric restriction attenuates amyloid deposition in middle-aged dtg APP/PS1 mice

Caloric restriction (CR) mitigates neurological damage arising from aging and a variety of other sources, including neuropathology in young adult mice that express single and double transgenic (tg) mutations associated with Alzheimer disease (AD). To evaluate the potential of CR to protect against relatively heavy AD-type pathology, middle-aged (13–14-month-old) mice that co-express two mutations related to familial AD, amyloid precursor protein (APP) and presenilin 1 (PS1), were fed balanced diets with 40% fewer calories than ad libitum-fed controls. Following 18 weeks of treatment, mice were killed and brains were processed for quantification of total volume of amyloid-beta (Aβ) in the hippocampal formation and the overlying neocortex. Computerized stereology confirmed that CR reduced the total Aβ volume by about one-third compared to that in age-matched controls. Thus, CR appears to attenuate the accumulation of AD-type neuropathology in two cortical brain regions of middle-aged dtg APP/PS1 mice. These findings support the view that CR could be a potentially effective, non-pharmacology strategy for reducing relatively heavy Aβ deposition in older adult dtg APP/PS1 mice, and possibly afford similar protection against the onset and progression of AD in older adult humans.