Effects of microglial depletion and TREM2 deficiency on A\u03b2 plaque burden and neuritic plaque tau pathology in 5XFAD mice

Argyro Thalia Delizannis,Ilse Van Den Wyngaert,Virginia M.-Y Lee,Annelies Nonneman,Shaniya Maimaiti,Modupe F Olufemi,Kurt R Brunden,An De Bondt,Bin Zhang,John Q Trojanowski,Emily Meymand,Wangchen Tsering,Pyry Koivula

doi:10.1186/s40478-021-01251-1

Abstract

Dystrophic neuronal processes harboring neuritic plaque (NP) tau pathology are found in association with Aβ plaques in Alzheimer’s disease (AD) brain. Microglia are also in proximity to these plaques and microglial gene variants are known risk factors in AD, including loss-of-function variants of TREM2. We have further investigated the role of Aβ plaque-associated microglia in 5XFAD mice in which NP tau pathology forms after intracerebral injection of AD brain-derived pathologic tau (AD-tau), focusing on the consequences of reduced TREM2 expression and microglial depletion after treatment with the colony-stimulating factor 1 (CSFR1) inhibitor, PLX3397. Young 5XFAD mice treated with PLX3397 had a large reduction of brain microglia, including cortical plaque-associated microglia, with a significant reduction of Aβ plaque burden in the cortex. A corresponding decrease in cortical APP-positive dystrophic processes and NP tau pathology were observed after intracerebral AD-tau injection in the PLX3397-treated 5XFAD mice. Consistent with prior reports, 5XFAD × TREM2−/− mice showed a significant reduction of plaque-associated microglial, whereas 5XFAD × TREM2+/− mice had significantly more plaque-associated microglia than 5XFAD × TREM2−/− mice. Nonetheless, AD-tau injected 5XFAD × TREM2+/− mice showed greatly increased AT8-positive NP tau relative to 5XFAD × TREM2+/+ mice. Expression profiling revealed that 5XFAD × TREM2+/− mice had a disease-associated microglial (DAM) gene expression profile in the brain that was generally intermediate between 5XFAD × TREM2+/+ and 5XFAD × TREM2−/− mice. Microarray analysis revealed significant differences in cortical and hippocampal gene expression between AD-tau injected 5XFAD × TREM2+/− and 5XFAD × TREM2−/− mice, including pathways linked to microglial function. These data suggest there is not a simple correlation between the extent of microglia plaque interaction and plaque-associated neuritic damage. Moreover, the differences in gene expression and microglial phenotype between TREM2+/− and TREM2−/− mice suggest that the former may better model the single copy TREM2 variants associated with AD risk.

Highlights

The key pathological hallmarks of the Alzheimer’s disease (AD) brain are extracellular senile plaques comprising Aβ peptides and intracellular inclusions of misfolded tau protein, which normally binds microtubules (MTs) [9, 17]
A recent report has revealed that TREM2 KO, or expression of human R47H TREM2 on a mouse TREM2 null background, results in exacerbation of neuritic plaque (NP) tau pathology after AD brainderived pathologic tau (AD-tau) injection of APP/ PS1 mice [28], we extend these studies by comparing the effects of both T REM2−/− and T REM2−/+ microglia in AD-tau-injected 5XFAD mice
Depletion of microglia in young 5XFAD mice prior to intracerebral AD‐tau seeding Recent publications revealed that depletion of microglia from young 5XFAD mice with colony-stimulating factor 1 (CSFR1) inhibitors led to a reduction of parenchymal Aβ plaques [37, 38], albeit with the extent of plaque lowering differing between studies

Summary

Introduction

The key pathological hallmarks of the AD brain are extracellular senile plaques comprising Aβ peptides and intracellular inclusions of misfolded tau protein, which normally binds microtubules (MTs) [9, 17]. Tau inclusions have been strongly implicated in the neurodegeneration of AD, as multiple immunohistochemical studies reveal a significant correlation between the degree of tau pathology and cognitive deficits in AD patients [1, 4, 48], a relationship that is not observed with Aβ plaque burden. A key research objective is identifying mechanisms by which the formation of Aβ plaques promote the spread of neocortical tau pathology that is linked to AD dementia

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Results

Conclusion