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Effects of microglial depletion and TREM2 deficiency on Aβ plaque burden and neuritic plaque tau pathology in 5XFAD mice.

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.

SUBMITTER: Delizannis AT

PROVIDER: S-EPMC8428059 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundAlzheimer's disease (AD) is a neurodegenerative disorder that manifests sequential Aβ and tau brain pathology with age-dependent onset. Variants in the microglial immune receptor TREM2 are associated with enhanced risk of onset in sporadic Alzheimer's disease (AD). While recent studies suggest TREM2 dysfunction can aggravate tau pathology, mechanisms underlying TREM2-dependent modulation of tau pathology remains elusive.MethodsHere, we characterized differences in progressive tau spreading from the medial entorhinal cortex (MEC) to the hippocampus in wildtype (WT) and Trem2 knockout (KO) mice by injection of AAV-P301L tau into the MEC, and correlated changes in hippocampal tau histopathology with spatial and fear memory. We also compared effects of intraneuronal dispersion between cultured microglia and neurons using a microfluidic dispersion assay, analyzed differences in microglial tau trafficking following uptake, and quantified exosomal tau secretion and pathogenicity from purified WT and Trem2 KO exosomes.ResultsTrem2 deletion in mice (Trem2 KO) can enhance tau spreading from the medial entorhinal cortex (MEC) to the hippocampus, which coincides with impaired synaptic function and memory behavior. Trem2 deletion in microglia enhances intraneuronal dispersion of tau in vitro between neuronal layers cultured in a microfluidic chamber, and the presence of exosome inhibitors can significantly reduce tau in exosomes and extracellular media from tau-loaded microglia. Although microglial Trem2 deletion has no effect on tau uptake, Trem2 deletion enhances distribution to endosomal and cellular pre-exosomal compartments following internalization. Trem2 deletion has little effect on exosome size, however, proteomic analysis indicates that Trem2 deletion can modulate changes in the microglial proteomic landscape with tau and LPS/ATP treatment conditions associated with exosome induction. Furthermore, exosomes from Trem2 KO microglia show elevated tau levels, and feature enhanced tau-seeding capacity in a tau FRET reporter line compared to exosomes from WT microglia.ConclusionTogether, our results reveal a role for Trem2 in suppressing exosomal tau pathogenicity, and demonstrates that Trem2 deletion can enhance tau trafficking, distribution and seeding through microglial exosomes.

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Effects of microglial depletion and TREM2 deficiency on Aβ plaque burden and neuritic plaque tau pathology in 5XFAD mice.

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