CD45 Deficiency Drives Amyloid-β Peptide Oligomers and Neuronal Loss in Alzheimer's Disease Mice

Abstract

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.

Toll-like receptor 4 stimulation with the detoxified ligand monophosphoryl lipid A improves Alzheimer’s disease-related pathology

“…However, the increased proportion of CD45 + cells containing Aβ found in the brain of MPL-treated mice suggests that peripheral clearance is not the exclusive mechanism involved in eliminating Aβ. In this regard, it is noteworthy that CD45 + microglial cells have been shown to promote the clearance of oligomeric Aβ (34). A compatible mode of action could be the stimulation of microglia or macrophages located in the CVOs, which lay outside the blood-brain barrier (BBB).…”

Diosmin reduces cerebral Aβ levels, tau hyperphosphorylation, neuroinflammation, and cognitive impairment in the 3xTg-AD mice

“…Murine primary culture microglia were isolated from mouse cerebral cortices as described previously (Zhu et al, 2011a). Briefly, cerebral cortices from newborn mice (1–2-day old) were isolated under sterile conditions and mechanically dissociated at 4°C.…”

Microglia in Alzheimer’s disease: A multifaceted relationship

“…leukocyte common antigen (LCA)) in the brain of APPswe/PS1 dramatically increased cerebral soluble and insoluble Aβ load, and enhanced the production of pro-inflammatory cytokines by microglia that internalized Aβ, which exacerbated the neuronal injury (Zhu et al, 2011). These results outlined the crucial role of CD45 in modulating the immune response orchestrated by microglia following Aβ phagocytosis (Zhu et al, 2011).…”