Alzheimer disease (AD) is the most prominent cause of dementia in the elderly. To determine changes in the AD brain that may mediate the transition into dementia, the gene expression of approximately 10,000 full-length genes was compared in mild/moderate dementia cases to non-demented controls that exhibited high AD pathology. Including this latter group distinguishes this work from previous studies in that it allows analysis of early cognitive loss. Compared to non-demented high-pathology controls, the hippocampus of AD cases with mild/moderate dementia had increased gene expression of the inflammatory molecule major histocompatibility complex (MHC) II, as assessed with microarray analysis. MHC II protein levels were also increased and inversely correlated with cognitive ability. Interestingly, the mild/moderate AD dementia cases also exhibited decreased number of T cells in the hippocampus and the cortex compared to controls. In conclusion, transition into AD dementia correlates with increased MHC II + microglia-mediated immunity and is paradoxically paralleled by a decrease in T cell number, suggesting immune dysfunction.

Background: Inflammation is associated with Aβ pathology in Alzheimer's disease (AD) and transgenic AD models. Previously, it has been demonstrated that chronic stimulation of the immune response induces pro-inflammatory cytokines IL-1β and TNF-α which contribute to neurodegeneration. However, recent evidence has shown that inducing the adaptive immune response reduces Aβ pathology and is neuroprotective. Low concentrations of IFN-γ modulate the adaptive immune response by directing microglia to differentiate to antigen presenting cells. Our objective was to determine if exercise could induce a shift from the immune profile in aged (17-19 months) Tg2576 mice to a response that reduces Aβ pathology.

Exercise is a treatment paradigm that can ameliorate cognitive dysfunction in Alzheimer disease (AD) and AD mouse models. Since exercise is also known to alter the peripheral immune response, one potential mechanism for the cognitive improvement following exercise may be by modulating the inflammatory repertoire in the central nervous system. We investigated the effects of voluntary exercise in the Tg2576 mouse model of AD at a time-point at which pathology has already developed. Inflammatory mRNA markers are increased in sedentary Tg2576 mice versus non-transgenic controls. We demonstrate that short-term voluntary wheel running improved spatial learning in aged transgenic mice as compared to sedentary Tg2576 controls. Inflammatory profiles of the Tg2576 and non-transgenic mice were different following exercise with the non-transgenic mice showing a broader response as compared to the Tg2576. Notably, exercising Tg2576 exhibited increases in a few markers including CXCL1 and CXCL12, two chemokines that may affect cognition.

During the past 2 decades, the elucidation of susceptibility and causative genes for Alzheimer disease as well as proteins involved in the pathogenic process has greatly facilitated the development of genetically altered mouse models. These models have played a major role in defining critical disease-related mechanisms and in evaluating novel therapeutic approaches, with many treatments currently in clinical trial owing their origins to studies initially performed in mice. This review discusses the utility of transgenic mice as a research tool and their contributions to our understanding of Alzheimer disease.The most common cause of dementia, AD 2 accounts for 60 -70% of all dementia cases and afflicts Ͼ15 million individuals worldwide. The disorder is characterized by severe memory loss, with episodic memory being particularly impaired during the initial phases. At present, the disorder is not curable. Most AD cases occur sporadically (SAD), although inheritance of certain susceptibility genes enhances the risk. A small minority of AD cases (Ͻ1%) is inheritable (referred to as FAD) and is caused by mutations in genes encoding APP, PS1, or PS2. Pathological Hallmarks of ADDefinitive diagnosis of AD occurs during post-mortem examination upon detection of two hallmark pathologies. The first is amyloid plaques, which consist of A␤. The length of A␤ can vary, but a 42-amino acid variant is considered neurotoxic because of its propensity to readily aggregate into oligomers and fibrils. All mutations associated with FAD affect the aggregation and/or production of A␤, which is sequentially cleaved from the APP holoprotein, first by an enzyme known as BACE (beta-APP-cleaving enzyme) and then by an enzymatic complex known as ␥-secretase, in which the presenilins form the catalytic core (1). FAD-associated mutations in APP cluster around the ␤-secretase cleavage site (e.g. Swedish mutation), in key amino acids affecting its ability to aggregate (e.g. Arctic and Dutch mutations), or around the ␥-secretase cleavage site, which increases production of the longer A␤42 peptide (e.g. London mutation). PS mutations play a similar role by favoring production of A␤42 at the expense of A␤40. In vitro experiments and transgenic mice have shown us that the aggregation state of A␤ is crucial, that it can also accumulate intraneuronally, and that it can mediate a diverse range of pathological effects on cellular function (2).The second pathological hallmark is the appearance of intraneuronal aggregates composed of the microtubule-associated protein tau. Hyperphosphorylation of tau leads it to dissociate from the microtubules and aggregate within the axoplasm as NFTs (3). Furthermore, tau dissociation leads to a reduction in microtubule stability and impaired axonal transport, ultimately leading to neuronal dysfunction and loss of synapses and subsequent retrograde degeneration (4). Mutations in the gene for tau (MAPT) are not associated with AD but cause FTDP-17 (frontal temporal dementia with parkinsonism 17), showing that disruption ...