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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
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1956.full.pdf
Description
Published version
Size
6.72 MB
Format
Adobe PDF
Checksum (MD5)
739467be46a963ee33edd08ac70eddaa
Author(s)
Meilandt, William J
Ngu, Hai
Gogineni, Alvin
Lalehzadeh, Guita
Lee, Seung-Hye
Srinivasan, Karpagam
Imperio, Jose
Wu, Tiffany
Weber, Martin
Kruse, Agatha J
Date Issued
2020
Journal
Journal of Neuroscience
Publisher
Society for Neuroscience
Version
Final published version
Abstract
Copyright © 2020 Meilandt et al. TREM2 is an Alzheimer’s disease (AD) risk gene expressed in microglia. To study the role of Trem2 in a mouse model of β-amyloidosis, we compared PS2APP transgenic mice versus PS2APP mice lacking Trem2 (PS2APP;Trem2 ko) 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;Trem2 ko 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;Trem2 ko brains, and the Aβ42:Aβ40 ratio was elevated. The amount of soluble, fibrillar Aβ oligomers also increased in PS2APP;Trem2 ko hippocampi. Associated with these changes, axonal dystrophy was exacerbated from 6 to 7 months onward in PS2APP;Trem2 ko mice, notwithstanding the reduced plaque load at later ages. PS2APP;Trem2 ko 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 Aβ into dense plaque is an important neuroprotective activity.
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Creative Commons Attribution 4.0 International license
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DOI of Published Version
10.1523/JNEUROSCI.1871-19.2019
