RT Journal Article
SR Electronic
T1 CD45 Deficiency Drives Amyloid-β Peptide Oligomers and Neuronal Loss in Alzheimer's Disease Mice
JF The Journal of Neuroscience
JO J. Neurosci.
FD Society for Neuroscience
SP 1355
OP 1365
DO 10.1523/JNEUROSCI.3268-10.2011
VO 31
IS 4
A1 Yuyan Zhu
A1 Huayan Hou
A1 Kavon Rezai-Zadeh
A1 Brian Giunta
A1 Amanda Ruscin
A1 Carmelina Gemma
A1 JingJi Jin
A1 Natasa Dragicevic
A1 Patrick Bradshaw
A1 Suhail Rasool
A1 Charles G. Glabe
A1 Jared Ehrhart
A1 Paula Bickford
A1 Takashi Mori
A1 Demian Obregon
A1 Terrence Town
A1 Jun Tan
YR 2011
UL http://www.jneurosci.org/content/31/4/1355.abstract
AB 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-β peptide (Aβ) but deficient in CD45 (PSAPP/CD45−/− mice) faithfully recapitulate AD neuropathology. Specifically, we find increased abundance of cerebral intracellular and extracellular soluble oligomeric and insoluble Aβ, decreased plasma soluble Aβ, increased abundance of microglial neurotoxic cytokines tumor necrosis factor-α and interleukin-1β, and neuronal loss in PSAPP/CD45−/− 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-Aβ phagocytic but proinflammatory microglial phenotype. This form of microglial activation occurs with elevated Aβ 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−/− mice. These data show that deficiency in CD45 activity leads to brain accumulation of neurotoxic Aβ oligomers and validate CD45-mediated microglial clearance of oligomeric Aβ as a novel AD therapeutic target.