Converging lines of evidence indicate dysregulation of the key immunoregulatory molecule CD45 (also known as leukocyte common antigen) in Alzheimer's disease (AD). We report that transgenic mice overproducing amyloid-␤ peptide (A␤) but deficient in CD45 (PSAPP/CD45Ϫ/Ϫ mice) faithfully recapitulate AD neuropathology. Specifically, we find increased abundance of cerebral intracellular and extracellular soluble oligomeric and insoluble A␤, decreased plasma soluble A␤, increased abundance of microglial neurotoxic cytokines tumor necrosis factor-␣ and interleukin-1␤, and neuronal loss in PSAPP/CD45 Ϫ/Ϫ mice compared with CD45-sufficient PSAPP littermates (bearing mutant human amyloid precursor protein and mutant human presenilin-1 transgenes). After CD45 ablation, in vitro and in vivo studies demonstrate an anti-A␤ phagocytic but proinflammatory microglial phenotype. This form of microglial activation occurs with elevated A␤ oligomers and neural injury and loss as determined by decreased ratio of anti-apoptotic Bcl-xL to proapoptotic Bax, increased activated caspase-3, mitochondrial dysfunction, and loss of cortical neurons in PSAPP/CD45 Ϫ/Ϫ mice. These data show that deficiency in CD45 activity leads to brain accumulation of neurotoxic A␤ oligomers and validate CD45-mediated microglial clearance of oligomeric A␤ as a novel AD therapeutic target.

Extracellular plaques of β-amyloid (Aβ) peptides are implicated in Alzheimer's Disease (AD) pathogenesis. Aβ formation is precluded by α-secretase, which cleaves within the Aβ domain of APP generating soluble APP-α(sAPP-α). Thus, α-secretase upregulation may be a target AD therapy. We previously showed green tea derived EGCG increased sAPP-α in AD mouse models. However, the comparable effective dose of EGCG in humans may exceed clinical convenience and/or safety. Epidemiological studies suggested fish oil consumption is associated with reduced dementia risk. Here we investigated whether oral co-treatment with fish oil (8 mg/kg/day) and EGCG (62.5 mg/kg/day, or 12.5 mg/kg/day) would reduce AD-like pathology in Tg2657 mice. In vitro co-treatment of N2a cells with fish oil and EGCG enhanced sAPP-α production compared to either compound alone (P<.001). Fish oil enhanced bioavailability of EGCG versus EGCG treatment alone (P<.001). Fish oil and EGCG had a synergetic effect on inhibition of cerebral Aβ deposits (P<.001) suggesting moderate supplementation with EGCG and fish oil have significant therapeutic potential for treatment of AD.

Alzheimer's disease (AD) is the most common progressive neurodegenerative brain disease as well as the most common dementia among the elderly. In the future as the average lifespan continues to extend, the number of AD patients will continue to grow. Amyloidbeta (Aβ) peptides, in both soluble oligomeric, and insoluble forms, are key in the neuropathogenesis of AD and have thus been a therapeutic target for vaccines. Multiple Aβ vaccination strategies in animal models of AD have demonstrated a marked reduction in both amyloid burden and neurocognitive deficits. Due to the success of these studies, initial human clinical trials of an active Aβ vaccine were conducted. These were discontinued due to the development of meningoencephalitis in approximately 6% of the vaccinated AD patients. Studies examining the brains of Aβ-vaccinated patients developing meningoencephalitis implicate Aβ-reactive T-cell subsets as major components of this deleterious response to active Aβ vaccination. To subvert possible meningoencephalitis resulting from Aβ vaccination a second generation of vaccines has been more recently developed. These however have met with little success in humans. To build on these findings, an understanding of the role of T-cells in vaccination against Aβ is presented in this review. Various methods of Aβ immunotherapy are reviewed including studies in both animal models and humans. Recent works suggest that Aβ-derived peptides delivered intranasally or transcutaneously results in effective clearance of Aβ plaques and improvement of cognitive function in animal models of AD. Moreover, undesired T-cell reactivity appeared to be considerably reduced compared with other active immunization strategies. In spite of the past clinical studies, these findings imply that Aβ vaccination may be both efficacious and safe depending route of delivery, adjuvant choice, and Aβ epitope administered.