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P1‐022: Suspected NON‐AD Pathology in Mild Cognitive Impairment: Defined by Cross‐Sectional or Longitudinal Neurodegeneration
Author(s) -
Wisse Laura E.M.,
Das Sandhitsu,
Yushkevich Paul A.,
Wolk David
Publication year - 2016
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2016.06.769
Subject(s) - neurodegeneration , medicine , dementia , atrophy , cross sectional study , alzheimer's disease , cognitive impairment , disease , pathology , neuroscience , psychology
Background: Neuroinflammation in the course of Alzheimer’s disease (AD) serves to exacerbate AD and promote disease progression. Amyloid Beta (AB) peptides and plaques are highly cytotoxic and trigger chronic inflammation in the cellular environment, contributing to the infiltration of macrophages within the brain. Upon activation, macrophages release pro-inflammatory cytokines that promote further neurotoxicity and apoptosis associated with AD. A major impediment to investigating neuroinflammation involving macrophage activity is the inability to discriminate between CNS-resident microglia-derived macrophages (mM) and hematogenous monocyte-derived macrophages (hM) in a temporal and spatial manner as these two populations of macrophages are morphologically and phenotypically similar in the activated state. Therefore, the overall goal of this research is to distinguish between hM and mM, and determine their respective roles in chronic inflammation associated with AD progression. Methods:The lys-EGFP-ki transgenic mouse line that enables the discrimination between mM and hMwas crossed with 5xFADmice. The resultant LysFADmice exhibited aggressive AD pathology of 5xFAD mice while enabling the spatial and temporal discrimination of mM and hM in the brain. Plaque load in the brains of these mice was measured using ELISA for AB42 in the cortex and hippocampus and spatial learning and memory was assessed using theMorrisWaterMaze.Results: Levels of AB42 were significantly higher in the brains of male and female LysFAD + compared to LysFAD littermates at 1.5 and 3 months, with AB levels peaking at 5 months and reaching a plateau by 7 months of age. Additionally, LysFAD+ male and female mice demonstrated spatial learning and memory deficits as measured by the Morris Water Maze test, at 5 and 7 months of age with deficits more pronounced in females. Conclusions: Based on these results, the time of onset of the behavioral deficits and accumulation of AB42 in the brains of LysFAD+ mice was identified to be 5-7 months. Therefore, immunostaining with specific antibodies for GFP, Iba1 (marker of microglia/macrophages) and AB plaques will be performed on frozen brain sections of these 5-7 month old mice in order to determine whether the macrophages surrounding AB plaques are hematogenous in origin or microglia-derived.