Frontobasal gray matter loss is associated with the TREM2 p.R47H variant

A rare heterozygous TREM2 variant p.R47H (rs75932628) has been associated with an increased risk for Alzheimer's disease (AD). We aimed to investigate the clinical presentation, neuropsychological profile, and regional pattern of gray matter and white matter loss associated with the TREM2 variant p.R47H, and to establish which regions best differentiate p.R47H carriers from noncarriers in 2 sample sets (Spanish and Alzheimer's Disease Neuroimaging Initiative, ADNI1). This was a cross-sectional study including a total number of 16 TREM2 p.R47H carriers diagnosed with AD or mild cognitive impairment, 75 AD p.R47H noncarriers and 75 cognitively intact TREM2 p.R47H noncarriers. Spanish AD TREM2 p.R47H carriers showed apraxia (9 of 9) and psychiatric symptoms such as personality changes, anxiety, paranoia, or fears more frequently than in AD noncarriers (corrected p = 0.039). For gray matter and white matter volumetric brain magnetic resonance imaging voxelwise analyses, we used statistical parametric mapping (SPM8) based on the General Linear Model. We used 3 different design matrices with a full factorial design. Voxel-based morphometry analyses were performed separately in the 2 sample sets. The absence of interset statistical differences allowed us to perform joint and conjunction analyses. Independent voxel-based morphometry analysis of the Spanish set as well as conjunction and joint analyses revealed substantial gray matter loss in orbitofrontal cortex and anterior cingulate cortex with relative preservation of parietal lobes in AD and/or mild cognitive impairment TREM2 p.R47H carriers, suggesting that TREM2 p.R47H variant is associated with certain clinical and neuroimaging AD features in addition to the increased TREM2 p.R47H atrophy in temporal lobes as described previously. The high frequency of pathologic behavioral symptoms, combined with a preferential frontobasal gray matter cortical loss, suggests that frontobasal and temporal regions could be more susceptible to the deleterious biological effects of the TREM2 variant p.R47H.     

Age-related expression of STUB1 in senescence-accelerated mice and its response to anti-Alzheimer's disease traditional Chinese medicine

Increasing evidences have indicated that STUB1 may be closely linked to Alzheimer's disease (AD). Senescence-accelerated mice (SAM) prone/8 (SAMP8) is a generally acknowledged animal model for senescence and AD, and SAM resistant/1 (SAMR1) is its control. In this study, we investigated the detailed expression of STUB1 in the brain of SAMP8 with aging and its responses to five anti-AD traditional Chinese medicinal (TCM), using real-time fluorescence quantitative PCR and Western blot technique. Results showed that with the aging process, both mRNA and protein expression of STUB1 in the cerebral cortex and hippocampus from SAMR1 increased after 2 months, while they decreased in brain tissues from SAMP8 after 6 months. Compared with SAMR1, the mRNA and protein expression of STUB1 decreased after 10 months in SAMP8 but could be up-regulated by the five anti-AD TCM used in this study. These results indicated that the expression of STUB1 in the brain of SAMP8 was abnormal and this abnormality could be reversed by anti-AD TCM. The data suggested that a deficiency in STUB1 may lead to a reduction in aberrant protein scavenging, causing abnormal protein accumulation in the brain of SAMP8. Thus, STUB1 might be a potential target for anti-AD TCM.     

Efflux of human and mouse amyloid beta proteins 1-40 and 1-42 from brain: impairment in a mouse model of Alzheimer's disease

Brain to blood transport is believed to be a major determinant of the amount of amyloid beta protein (AbetaP) found in brain. Impaired efflux has been suggested as a mechanism by which AbetaP can accumulate in the CNS and so lead to Alzheimer's disease (AD). To date, however, no study of the efflux of the form of AbetaP most relevant to AD, AbetaP1-42, has been conducted, even though a single amino acid substitution in AbetaP can greatly alter efflux. Here, we examined the efflux of AbetaP mouse1-42, mouse1-40, human1-42, and human1-40 in young CD-1, young senesence accelerated mouse (SAM) P8, and aged SAMP8 mice. The SAMP8 mouse with aging spontaneously overproduces AbetaP and develops cognitive impairments reversed by AbetaP-directed antibody or phosphorothioate antisense oligonucleotide. CD-1 mice transported all forms of AbetaP, although mouse1-42 and human1-40 were transported faster than the other forms. There was a decrease in the saturable transport of mouse1-42 in SAMP8 mice regardless of age. Efflux of mouse1-40 and human1-42 was only by a non-saturable mechanism in young SAMP8 mice and their efflux was totally absent in aged SAMP8 mice. These differences in the efflux of the various forms of AbetaP among the three groups of mice supports the hypothesis that impaired efflux is an important factor in the accumulation of AbetaP in the CNS.     

The behavioral,pathological and therapeutic features of the senescence-accelerated mouse prone 8 strain as an Alzheimer's disease animal model

Alzheimer's disease (AD) is a widespread and devastating progressive neurodegenerative disease. Disease-modifying treatments remain beyond reach, and the etiology of the disease is uncertain. Animal model are essential for identifying disease mechanisms and developing effective therapeutic strategies. Research on AD is currently being carried out in rodent models. The most common transgenic mouse model mimics familial AD, which accounts for a small percentage of cases. The senescence-accelerated mouse prone 8 (SAMP8) strain is a spontaneous animal model of accelerated aging. Many studies indicate that SAMP8 mice harbor the behavioral and histopathological signatures of AD, namely AD-like cognitive and behavioral alterations, neuropathological phenotypes (neuron and dendrite spine loss, spongiosis, gliosis and cholinergic deficits in the forebrain), β-amyloid deposits resembling senile plaques, and aberrant hyperphosphorylation of Tau-like neurofibrillary tangles. SAMP8 mice are useful in the development of novel therapies, and many pharmacological agents and approaches are effective in SAMP8 mice. SAMP8 mice are considered a robust model for exploring the etiopathogenesis of sporadic AD and a plausible experimental model for developing preventative and therapeutic treatments for late-onset/age-related AD, which accounts for the vast majority of cases.     

Acupuncture improves cognitive deficits and regulates the brain cell proliferation of SAMP8 mice

Senescence-accelerated mouse prone 8 (SAMP8) is an autogenic senile strain characterized by early cognitive impairment and age-related deterioration of learning and memory. To investigate the effect of acupuncture on behavioral changes and brain cell events, male 4-month-old SAMP8 and age-matched homologous normal aging SAMR1 mice were divided into four groups: SAMP8 acupuncture group (Pa), SAMP8 non-acupoint control group (Pn), SAMP8 control group (Pc) and SAMR1 normal control group (Rc). By Morris water maze test, the cognitive deficit of SAMP8 was revealed and significantly improved by "Yiqitiaoxue and Fubenpeiyuan" acupuncture. Meanwhile, by 5'-bromo-2'-deoxyuridine (BrdU) specific immunodetection, the decreased cell proliferation in dentate gyrus (DG) of SAMP8 was greatly enhanced by the therapeutic acupuncture, suggesting acupoint-related specificity. Even though no significant differences were found in ventricular/subventricular zones (VZ/SVZ) of the third ventricle (V3) and lateral ventricle (LV) between groups, we obtained interesting results: a stream-like distribution of newly proliferated cells presented along the dorsum of alveus hippocampi (Alv), extending from LV to corpus callosum (CC), and the therapeutic acupuncture showed a marked effect on this region. Our research suggests that acupuncture can induce different cell proliferation in different brain regions of SAMP8, which brings forth the need to explore further for the mechanism of cognitive deficits and acupuncture intervention in this field.     

Monocyte chemoattractant protein-1 plays a dominant role in the chronic inflammation observed in Alzheimer's disease

Chronic neuroinflammation correlates with cognitive decline and brain atrophy in Alzheimer's disease (AD), and cytokines and chemokines mediate the inflammatory response. However, quantitation of cytokines and chemokines in AD brain tissue has only been carried out for a small number of mediators with variable results. We simultaneously quantified 17 cytokines and chemokines in brain tissue extracts from controls (n = 10) and from patients with and without genetic forms of AD (n = 12). Group comparisons accounting for multiple testing revealed that monocyte chemoattractant protein-1 (MCP-1), interleukin-6 (IL-6) and interleukin-8 (IL-8) were consistently upregulated in AD brain tissue. Immunohistochemistry for MCP-1, IL-6 and IL-8 confirmed this increase and determined localization of these factors in neurons (MCP-1, IL-6, IL-8), astrocytes (MCP-1, IL-6) and plaque pathology (MCP-1, IL-8). Logistic linear regression modeling determined that MCP-1 was the most reliable predictor of disease. Our data support previous work on significant increases in IL-6 and IL-8 in AD but indicate that MCP-1 may play a more dominant role in chronic inflammation in AD.     

Repeated administration of the noradrenergic neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) modulates neuroinflammation and amyloid plaque load in mice bearing amyloid precursor protein and presenilin-1 mutant transgenes

Background

Data indicates anti-oxidant, anti-inflammatory and pro-cognitive properties of noradrenaline and analyses of post-mortem brain of Alzheimer's disease (AD) patients reveal major neuronal loss in the noradrenergic locus coeruleus (LC), the main source of CNS noradrenaline (NA). The LC has projections to brain regions vulnerable to amyloid deposition and lack of LC derived NA could play a role in the progression of neuroinflammation in AD. Previous studies reveal that intraperitoneal (IP) injection of the noradrenergic neurotoxin N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) can modulate neuroinflammation in amyloid over-expressing mice and in one study, DSP-4 exacerbated existing neurodegeneration.

Methods

TASTPM mice over-express human APP and beta amyloid protein and show age related cognitive decline and neuroinflammation. In the present studies, 5 month old C57/BL6 and TASTPM mice were injected once monthly for 6 months with a low dose of DSP-4 (5 mg kg^-1) or vehicle. At 8 and 11 months of age, mice were tested for cognitive ability and brains were examined for amyloid load and neuroinflammation.

Results

At 8 months of age there was no difference in LC tyrosine hydroxylase (TH) across all groups and cortical NA levels of TASTPM/DSP-4, WT/Vehicle and WT/DSP-4 were similar. NA levels were lowest in TASTPM/Vehicle. Messenger ribonucleic acid (mRNA) for various inflammatory markers were significantly increased in TASTPM/Vehicle compared with WT/Vehicle and by 8 months of age DSP-4 treatment modified this by reducing the levels of some of these markers in TASTPM. TASTPM/Vehicle showed increased astrocytosis and a significantly larger area of cortical amyloid plaque compared with TASTPM/DSP-4. However, by 11 months, NA levels were lowest in TASTPM/DSP-4 and there was a significant reduction in LC TH of TASTPM/DSP-4 only. Both TASTPM groups had comparable levels of amyloid, microglial activation and astrocytosis and mRNA for inflammatory markers was similar except for interleukin-1 beta which was increased by DSP-4. TASTPM mice were cognitively impaired at 8 and 11 months but DSP-4 did not modify this.

Conclusion

These data reveal that a low dose of DSP-4 can have varied effects on the modulation of amyloid plaque deposition and neuroinflammation in TASTPM mice dependent on the duration of dosing.     

Amelioration of cognitive ability in senescence-accelerated mouse prone 8 (SAMP8) by intra-bone marrow-bone marrow transplantation

Bone marrow cells (BMCs) can increase the number of activated microglias, which play a central role in the inflammatory response in Alzheimer's disease (AD). Senescence-accelerated mouse (SAM) prone 8 (SAMP8) are widely used in various experiments because of cognitive deficits observed with age. In the present study, 4-month-old SAMP8 were reconstituted with BMCs of C57BL/6 mice by intra-bone marrow-bone marrow transplantation (IBM-BMT), which can reconstitute both donor-derived hemopoietic stem cells and mesenchymal stem cells. Three months after IBM-BMT, the impairment of spatial memory in SAMP8 was found to be ameliorated after analyzing the results of the water maze test. Although IL-1β, IL-6 and iNOS increased and TGF-β decreased in 7 M SAMP8, IL-1β, IL-6 and iNOS decreased while TGF-β increased after IBM-BMT by RT-PCR. Moreover, oxidative stress-related heme oxygenase-1 (HO-1) increased in 7 M SAMP8, but significantly decreased after IBM-BMT. In conclusion, this is the first report suggesting that the impaired cognitive ability of SAMP8 is ameliorated by IBM-BMT. It seems likely that decreases in IL-1β, IL-6, iNOS and HO-1 are a result of the development of donor-derived BMCs.     

Respiratory infection promotes T cell infiltration and amyloid-β deposition in APP/PS1 mice

Alzheimer's disease (AD) is a progressive neurodegenerative disease characterized by deposits of amyloid-β and neurofibrillary tangles. It has been suggested that inflammatory changes are associated with disease; however, it has not been established whether these are a consequence of ongoing neurodegeneration or whether inflammation itself contributes to disease pathogenesis. Recent studies suggest that exposure to infection can accelerate cognitive decline in AD patients, and pathogens have been detected in the AD brain. However, the influence of infection on neuroinflammation and pathology remains poorly understood. In this study, we examined the effect of a peripheral infection on AD pathology in APP/PS1 mice. We found that, 8 weeks after infection with the Gram negative respiratory pathogen Bordetella pertussis, there was significant infiltration of IFNγ- and IL-17–producing T cells and NKT cells in older APP/PS1 mice. This was accompanied by increased glial activation and amyloid-β deposition. The data suggest that infection is a critical factor in the progression of AD, emphasising the importance of early diagnosis and treatment of infections in elderly individuals.     

Chronic stress impairs learning and hippocampal cell proliferation in senescence-accelerated prone mice

Chronic stress can induce cognitive impairment. It is unclear whether a higher susceptibility to chronic stress is associated with the progression of pathological brain aging. Senescence-accelerated prone mouse 8 (SAMP8) is a naturally occurring animal model of accelerated brain aging. Senescence-accelerated resistant mouse 1 (SAMR1) is usually used as the normal control. In this study, we examined the effects of chronic restraint stress (CRS) on learning in the Y-maze, hippocampal cell proliferation, and the expression of brain-derived neurotrophic factor (BDNF) in the hippocampus of 4-month-old SAMP8 and SAMR1. The results showed that exposure to CRS impaired learning and hippocampal cell proliferation in SAMP8 and SAMR1 but to a much greater extent in SAMP8. Furthermore, CRS significantly decreased the expression of BDNF protein and mRNA in the hippocampus of SAMP8 and SAMR1. These data indicated that SAMP8 is more sensitive to the deleterious effects of CRS on learning than SAMR1. A greater decrease in hippocampal cell proliferation caused by chronic stress may be part of the underlying mechanism for the more severe learning deficit observed in SAMP8. In addition, our findings suggested a role of BDNF in the stress-induced impairment of learning and hippocampal cell proliferation in both strains.     

Differential gene expression profiles in the hippocampus of senescence-accelerated mouse

The senescence-accelerated mouse (SAM) is an animal model for studying senescence and age-associated disorders due to its inherited aging phenotype. The SAM/prone8 (SAMP8) is a useful animal model to investigate the fundamental mechanisms involved in age-related learning and memory deficits that may have relevance to age-associated AD, while SAM/resistant1 (SAMR1) shows normal. To identify genes rendering the cognitive deterioration with aging, the subtractive cDNA libraries containing 1924 clones with the positive ratio of 96.18% were generated and the microarray containing 3136 cDNA was prepared. The results of screening libraries by the microarray showed that of all 91 differentially expressed genes, 50 were over-expressed and 41 were low-expressed in SAMP8. Some of the identified genes were confirmed by the real time quantitative RT-PCR. These results indicated the profiles of gene expression in the hippocampus of SAMP8 and SAMR1 were significantly different, which may play important roles in the age-related cognitive deficit in SAMP8, suggesting those genes related to the cognitive deficient or pathology change in the brain of SAMP8 may be potential gene targets for Alzheimer's disease therapy.     

Multiple inflammatory pathways are involved in the development and progression of cognitive deficits in APPswe/PS1dE9 mice

Increased accumulation of amyloid-beta peptide (Aβ) and neuroinflammation is known to exist within the Alzheimer's disease (AD) brain. However, it remains unclear which form of Aβ pathologies triggers neuroinflammation and whether increased neuroinflammation contributes to cognitive deficits in AD. In the present study we found that increased inflammatory responses might occur early in preplaque APPswe/PS1dE9 mice, and were significantly enhanced in both early- and late-plaque APPswe/PS1dE9 mice. Correlational analysis revealed that multiple inflammatory indexes significantly correlated with soluble Aβ level, rather than amyloid plaque burden or insoluble Aβ level, in APPswe/PS1dE9 mice. Moreover, multiple inflammatory indexes highly correlated with the impaired spatial learning and memory in APPswe/PS1dE9 mice. Collectively, these results provide evidence that inflammatory responses might be likely triggered by soluble toxic Aβ species. Importantly, we demonstrate for the first time that multiple inflammatory pathways might be involved in the development and progression of cognitive deficits in APPswe/PS1dE9 mice, suggesting that a pharmacological approach targeting multiple inflammatory pathways may be a novel promising strategy to prevent or delay AD.     

Investigation of triggering receptor expressed on myeloid cells 2 variant in the Wisconsin Registry for Alzheimer's Prevention

Recent studies have found an association between a variant in triggering receptor expressed on myeloid cells 2 (TREM2) (rs75932628-T) and both Alzheimer's disease (AD) and cognitive function in individuals aged 80–100 years. The role of TREM2 in younger, asymptomatic individuals is unknown. We examined this variant in 1148 participants from the Wisconsin Registry for Alzheimer's Prevention, a longitudinal study of middle-aged adults enriched for a parental history of AD. Thirteen individuals carried the T risk allele. Carriers were more likely to have a parental history of AD (100% of carriers vs. 70% of noncarriers; p = 0.01) and, among the parental history subset, families with a TREM2 carrier had a younger maternal age of AD onset than noncarriers (67.9 vs. 75.6 years; p = 0.03). There was no significant association between TREM2 carrier status and cognitive function or decline. In conclusion, the association between TREM2 and both parental history of AD and younger maternal age of AD onset provide additional support for the role of TREM2 in AD and illustrate the importance of considering family history in AD study design.     

Accelerated senescence prone mouse-8 shows early onset of deficits in spatial learning and memory in the radial six-arm water maze

Available data indicate that the senescence-accelerated prone mouse 8 (SAMP8) is an appropriate model of brain aging, with impairments in nonspatial learning and memory beginning as early as 2 months of age, and spatial learning and memory deficiencies not becoming apparent until after 4 months of age. However, with other strains (e.g., C57BL mice), the impairment in spatial memory was found earlier than that in nonspatial memory. We considered the possibility that the observed differences could be due to strain-specific differences in the training equipment. In the present study, a new optimized testing apparatus-the radial six-arm water maze (RAWM)-for detecting spatial learning and memory in mice, was employed, to determine whether there is impairment of spatial learning and memory in young SAMP8. The relationship between the spatial learning measures observed with the RAWM and the Morris maze, a classic spatial learning and memory testing apparatus, was also explored. It was found that, in the RAWM, rather than in the Morris maze, the impairment in spatial learning could be measured in SAMP8 mice as early as 3 months old, and the impairment in spatial memory in SAMP8 mice aged 5 months. These results suggested that the spatial learning and memory deficiencies could be found in early life of SAMP8 mice, and that RAWM and Morris maze each detect different aspects of spatial learning and memory.     

Lipid peroxidation in brain during aging in the senescence-accelerated mouse (SAM)

Accumulation of toxic amyloid-beta (Abeta)-peptide is suggested to cause oxidative stress in Alzheimer's disease (AD) brain, and decrease the content of polyunsaturated fatty acids (PUFA) in neuronal membrane lipids. The senescence accelerated prone mice (SAMP8) have age-related increases in the level of hippocampal Abeta-peptide, learning and memory deficits, and a shorter lifespan than their controls. The effects of age-related oxidative damage on PUFA content in membrane phospholipids (PL), and alpha-tocopherol concentration were investigated in hippocampus and amygdala of 2-, 4-, 12-, and 18-month-old SAMP8 mice. In comparison to the younger SAMP8 mice, the hippocampus of the 12-month-old mice contained lower proportions of docosahexaenoic acid (DHA) in phosphatidylserine (PS) and phosphatidylinositol (PI), and higher proportions of arachidonic acid (AA) in PS. Their amygdala contained a lower proportion of AA in phosphatidylcholine (PC). In the hippocampus of the oldest age group, the proportions of DHA in PS, and AA in PC and PI were higher than in the younger age groups. At 2 months of age, the amygdala contained a higher concentration of alpha-tocopherol than the hippocampus, but this difference between the two brain regions was lost with aging. The oldest age group contained the highest concentration of alpha-tocopherol, indicating a protection against oxidative damage of PUFA in brain membrane phospholipids.     

Murine leukemia virus in organs of senescence-prone and -resistant mouse strains

A series of inbred strains of mice have been developed that are either prone (SAMP) or resistant (SAMR) to accelerated senescence. All of these strains originated from an inadvertent cross or crosses between the AKR/J mouse strain and an unknown strain(s). The characteristics of the nine senescence-prone lines differ, with all strains showing generalized aspects of accelerated aging but with each line having a specific aging-related change that is emphasized, e.g. learning and memory deficits, osteoporosis and senile amyloidosis. The senescence-resistant strains have normal patterns of aging and do not show the specific aging-related changes seen in SAMP strains. The fact that AKR mice have high levels of endogenous, ecotropic murine leukemia virus (MuLV) prompted an examination of the expression levels of MuLV in SAM strains. Analysis of brain, spleen and thymus samples revealed that seven of nine SAMP strains had high levels of MuLV and contained the Emv11 provirus (previously termed Akv1) that encodes the predominant MuLV found in AKR mice. In contrast, none of the SAMR strains had Emv11 or significant amounts of virus. The current findings represent an initial step in determining the role of MuLV in the accelerated senescence seen in SAMP strains.     

Mitochondrial dysfunction,oxidative stress,neuroinflammation, and metabolic alterations in the progression of Alzheimer’s disease: A meta-analysis of in vivo magnetic resonance spectroscopy studies

Accumulating evidence demonstrates that metabolic changes in the brain associated with neuroinflammation, oxidative stress, and mitochondrial dysfunction play an important role in the pathophysiology of mild cognitive impairment (MCI) and Alzheimer’s disease (AD). However, the neural signatures associated with these metabolic alterations and underlying molecular mechanisms are still elusive. Accordingly, we reviewed the literature on in vivo human brain ¹H and ³¹P-MRS studies and use meta-analyses to identify patterns of brain metabolic alterations in MCI and AD. 40 and 39 studies on MCI and AD, respectively, were classified according to brain regions. Our results indicate decreased N-acetyl aspartate and creatine but increased myo-inositol levels in both MCI and AD, decreased glutathione level in MCI as well as disrupted energy metabolism in AD. In addition, the hippocampus shows the strongest alterations in most of these metabolites. This meta-analysis also illustrates progressive metabolite alterations from MCI to AD. Taken together, it suggests that 1) neuroinflammation and oxidative stress may occur in the early stages of AD, and likely precede neuron loss in its progression; 2) the hippocampus is a sensitive region of interest for early diagnosis and monitoring the response of interventions; 3) targeting bioenergetics associated with neuroinflammation/oxidative stress is a promising approach for treating AD.     

Sustained expression of interleukin-1β in mouse hippocampus impairs spatial memory

Glial activation and neuroinflammation occur in neurodegenerative disease and brain injury, however their presence in normal brain aging suggests that chronic neuroinflammation may be a factor in age-related dementia. Few studies have investigated the impact of sustained elevation of hippocampal interleukin-1β, a pro-inflammatory cytokine upregulated during aging and Alzheimer's disease, on cognition in mice. We utilized the IL-1β^XAT transgenic mouse to initiate bilateral hippocampal overexpression of interleukin-1β to determine the influence of sustained neuroinflammation independent of disease pathology. Fourteen days following transgene induction, adult male and female IL-1β^XAT mice were tested on non-spatial and spatial versions of the Morris water maze. For the spatial component, one retention trial was conducted 48 h after completion of a 3 day acquisition protocol (eight trials per day). Induction of IL-1β did not impact non-spatial learning, but was associated with delayed acquisition and decreased retention of the spatial task. These behavioral impairments were accompanied by robust reactive gliosis and elevated mRNA expression of inflammatory genes in the hippocampus. Our results suggest that prolonged neuroinflammation response per se may impact mnemonic processes and support the future application of IL-1β^XAT transgenic mice to investigate chronic neuroinflammation in age- and pathology-related cognitive dysfunction.     

Sleep wake profile and EEG spectral power in young or old senescence accelerated mice

Changes occurring with age in cortical EEG and sleep-wake states architecture were examined in senescence accelerated prone (SAMP8) or senescence resistant (SAMR1) mice (age: 2 and 12 months) under baseline conditions or after a 4 h sleep deprivation (SD). In baseline conditions, an increase in slow wave sleep (SWS) amount (21-24%) occurs at the expense of the wakefulness (W) in old SAMP8 and SAMR1 mice versus young animals. In these conditions, SWS latency is reduced (67-72%). Moreover, in SAMP8 and SAMR1 mice, aging deteriorates paradoxical sleep (PS) architecture with more pronounced changes in SAMP8 (amount: -63%; episode duration: -44%; latency: +286%; circadian component loss; and EEG theta (theta) peak frequency (TPF): -1 Hz). During the 4 h recovery subsequent to a 4 h sleep deprivation, old SAMP8 mice exhibit an enhanced sensitivity resulting in SWS (+62%) and PS (+120%) rebounds, a characteristic of this inbred strain. Results obtained are discussed in line with the age-related learning and memory impairments existing in SAMP8 animals. In particular, the reduced cognitive performances described in old SAMP8 might be linked to the TPF deterioration during PS.