학술논문
Trem2 Deletion Reduces Late-Stage Amyloid Plaque Accumulation, Elevates the Aβ42:Aβ40 Ratio, and Exacerbates Axonal Dystrophy and Dendritic Spine Loss in the PS2APP Alzheimer's Mouse Model.
Document Type
Article
Author
Meilandt, William J.; Hai Ngu; Gogineni, Alvin; Lalehzadeh, Guita; Seung-Hye Lee; Srinivasan, Karpagam; Imperio, Jose; Wu, Tiffany; Weber, Martin; Kruse, Agatha J.; Stark, Kimberly L.; Chan, Pamela; Kwong, Mandy; Modrusan, Zora; Friedman, Brad A.; Elstrott, Justin; Foreman, Oded; Easton, Amy; Sheng, Morgan; Hansen, David V.
Source
Subject
*AMYLOID plaque
*DENDRITIC spines
*DYSTROPHY
*TRANSGENIC mice
*ALZHEIMER'S disease
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Language
ISSN
0270-6474
Abstract
TREM2 is an Alzheimer's disease (AD) risk gene expressed in microglia. To study the role of Trem2 in a mouse model of/3-amyloidosis, we compared PS2APP transgenic mice versus PS2APP mice lacking Trem2 (PS2APP;Trem2ko) at ages ranging from 4 to 22 months. Microgliosis was impaired in PS2APP;Trem2 ko mice, with Trem2-deficient microglia showing compromised expression of proliferation/Wnt-related genes and marked accumulation of ApoE. Plaque abundance was elevated in PS2APP;Trem2ko females at 6 -7 months; but by 12 or 19-22 months of age, it was notably diminished in female and male PS2APP;Trem2 ko mice, respectively. Across all ages, plaque morphology was more diffuse in PS2APP;Trem2ko brains, and the A/342:A/340 ratio was elevated. The amount of soluble, fibrillar A/3 oligomers also increased in PS2APP;Trem2kH hippocampi. Associated with these changes, axonal dystrophy was exacerbated from 6 to 7 months onward in PS2APP;Trem2ko mice, notwithstanding the reduced plaque load at later ages. PS2APP;Trem2ko mice also exhibited more dendritic spine loss around plaque and more neurofilament light chain in CSF. Thus, aggravated neuritic dystrophy is a more consistent outcome of Trem2 deficiency than amyloid plaque load, suggesting that the microglial packing of A/3 into dense plaque is an important neuroprotective activity. [ABSTRACT FROM AUTHOR]