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

被引：120

作者：

Meilandt, William J. ^{[1
]}

Ngu, Hai ^{[2
]}

Gogineni, Alvin ^{[3
]}

Lalehzadeh, Guita ^{[1
]}

Lee, Seung-Hye ^{[1
]}

Srinivasan, Karpagam ^{[1
]}

Imperio, Jose ^{[1
]}

Wu, Tiffany ^{[1
]}

Weber, Martin ^{[1
]}

Kruse, Agatha J. ^{[3
]}

Stark, Kimberly L. ^{[1
]}

Chan, Pamela ^{[4
]}

Kwong, Mandy ^{[4
]}

Modrusan, Zora ^{[5
]}

Friedman, Brad A. ^{[6
]}

Elstrott, Justin ^{[3
]}

Foreman, Oded ^{[2
]}

Easton, Amy ^{[1
]}

Sheng, Morgan ^{[1
]}

Hansen, David, V ^{[1
]}

机构：

[1] Genentech Inc, Dept Neurosci, San Francisco, CA 94080 USA

[2] Genentech Inc, Dept Pathol, San Francisco, CA 94080 USA

[3] Genentech Inc, Dept Biomed Imaging, San Francisco, CA 94080 USA

[4] Genentech Inc, Dept Bioinformat, San Francisco, CA 94080 USA

[5] Genentech Inc, Dept Biochem & Cellular Pharmacol, San Francisco, CA 94080 USA

[6] Genentech Inc, Dept Mol Biol, San Francisco, CA 94080 USA

来源：

JOURNAL OF NEUROSCIENCE | 2020年 / 40卷 / 09期

关键词：

Alzheimer's disease; amyloid plaque; microglia; microgliosis; neuritic dystrophy; TREM2; WNT SIGNALING PATHWAY; MICROGLIAL ACTIVATION; DISEASE PROGRESSION; TRANSGENIC MICE; BETA PLAQUES; CATENIN; DEFICIENCY; BRAIN; EXPRESSION; PROTEIN;

D O I：

10.1523/JNEUROSCI.1871-19.2019

中图分类号：

Q189 [神经科学];

学科分类号：

071006 ;

摘要：

TREM2 is an Alzheimer's disease (AD) risk gene expressed in microglia. To study the role of Trem2 in a mouse model of beta-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 A beta 42:A beta 40 ratio was elevated. The amount of soluble, fibrillar A beta 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 A beta into dense plaque is an important neuroprotective activity.

引用

页码：1956 / 1974

页数：19

共 1 条

[1] Commentary: 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
Rai, Sachchida Nand
Chaturvedi, Vivek K.
Singh, Brijesh Kumar
Singh, Mohan P.
FRONTIERS IN AGING NEUROSCIENCE, 2020, 12

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