The Journal of neuroscience : the official journal of the Society for Neuroscience···
Removing Trem2 lowers late amyloid plaque buildup, increases harmful amyloid ratio, and worsens nerve fiber and spine damage in an Alzheimer's mouse model
PS2APP; mice showed impaired microgliosis and increased neuritic dystrophy despite reduced amyloid plaque accumulation at later ages.
Microglia in PS2APP;Trem2 mice had compromised expression of genes related to cell proliferation and marked accumulation of ApoE.
Plaque abundance was elevated in PS2APP;Trem2 females at 6-7 months but decreased in both sexes by 12-22 months.
Plaque morphology was more diffuse in PS2APP;Trem2 brains, with an elevated Aβ42:Aβ40 ratio and increased soluble, fibrillar Aβ oligomers.
Axonal dystrophy worsened from 6 to 7 months in PS2APP;Trem2 mice, indicating a strong relationship with microglial deficiency rather than amyloid plaque load.
Increased dendritic spine loss and neurofilament light chain in cerebrospinal fluid were observed in PS2APP;Trem2 mice, suggesting neuronal vulnerability.
Simplified
is an Alzheimer's disease (AD) risk gene expressed in microglia. To study the role ofin a mouse model of β-amyloidosis, we compared PS2APP transgenic mice versus PS2APP mice lacking(PS2APP;) at ages ranging from 4 to 22 months. Microgliosis was impaired in PS2APP;Trem2mice, with-deficient microglia showing compromised expression of proliferation/Wnt-related genes and marked accumulation of ApoE. Plaque abundance was elevated in PS2APP;Trem2females at 6-7 months; but by 12 or 19-22 months of age, it was notably diminished in female and male PS2APP;Trem2mice, respectively. Across all ages, plaque morphology was more diffuse in PS2APP;Trem2brains, and the Aβ42:Aβ40 ratio was elevated. The amount of soluble, fibrillar Aβ oligomers also increased in PS2APP;Trem2hippocampi. Associated with these changes, axonal dystrophy was exacerbated from 6 to 7 months onward in PS2APP;Trem2mice, notwithstanding the reduced plaque load at later ages. PS2APP;Trem2mice also exhibited more dendritic spine loss around plaque and more neurofilament light chain in CSF. Thus, aggravated neuritic dystrophy is a more consistent outcome ofdeficiency than amyloid plaque load, suggesting that the microglial packing of Aβ into dense plaque is an important neuroprotective activity.Genetic studies indicate thatgene mutations confer increased Alzheimer's disease (AD) risk. We studied the effects ofdeletion in the PS2APP mouse AD model, in which overproduction of Aβ peptide leads to amyloid plaque formation and associated neuritic dystrophy. Interestingly, neuritic dystrophies were intensified in the brains of-deficient mice, despite these mice displaying reduced plaque accumulation at later ages (12-22 months). Microglial clustering around plaques was impaired, plaques were more diffuse, and the Aβ42:Aβ40 ratio and amount of soluble, fibrillar Aβ oligomers were elevated in-deficient brains. These results suggest that the Trem2-dependent compaction of Aβ into dense plaques is a protective microglial activity, limiting the exposure of neurons to toxic Aβ species. TREM2Trem2Trem2Trem2Trem2TREM2Trem2Trem2Trem2ko ko ko ko ko ko ko ko SIGNIFICANCE STATEMENT
Key numbers
12 of 24 months
Decrease in Plaque Load
Reduced plaque accumulation observed in PS2APP; mice at older ages.
7 months
Increase in Axonal Dystrophy
Axonal dystrophy exacerbated from 7 months onward in PS2APP; mice.
2.3×
Elevated Aβ42:Aβ40 Ratio
Aβ42:Aβ40 ratio higher in PS2APP; brains across ages.
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