The effect of amyloid on microglia-neuron interactions before plaque onset occurs independently of TREM2 in a mouse model of Alzheimer’s disease

Genetic studies identified mutations in several immune-related genes that confer increased risk for developing Alzheimer's disease (AD), suggesting a key role for microglia in AD pathology. Microglia are recruited to and actively modulate the local toxicity of amyloid plaques in models of AD through these cells' transcriptional and functional reprogramming to a disease-associated phenotype. However, it remains unknown whether microglia actively respond to amyloid accumulation before plaque deposition in AD. We compared microglial interactions with neurons that exhibit amyloid accumulation to those that do not in 1-month-old 5XFAD mice to determine which aspects of microglial morphology and function are altered by early 6E10+ amyloid accumulation. We provide evidence of preferential microglial process engagement of amyloid laden neurons. Microglia, on exposure to amyloid, also increase their internalization of neurites even before plaque onset. Unexpectedly, we found that triggering receptor expressed on myeloid cells 2 (TREM2), which is critical for microglial responses to amyloid plaque pathology later in disease, is not required for enhanced microglial interactions with neurons or neurite internalization early in disease. However, TREM2 was still required for early morphological changes exhibited by microglia. These data demonstrate that microglia sense and respond to amyloid accumulation before plaques form using a distinct mechanism from the TREM2-dependent pathway required later in disease

Parkinson-causing α-synuclein missense mutations shift native tetramers to monomers as a mechanism for disease initiation

β-Sheet-rich α-synuclein (αS) aggregates characterize Parkinson's disease (PD). αS was long believed to be a natively unfolded monomer, but recent work suggests it also occurs in α-helix-rich tetramers. Crosslinking traps principally tetrameric αS in intact normal neurons, but not after cell lysis, suggesting a dynamic equilibrium. Here we show that freshly biopsied normal human brain contains abundant αS tetramers. The PD-causing mutation A53T decreases tetramers in mouse brain. Neurons derived from an A53T patient have decreased tetramers. Neurons expressing E46K do also, and adding 1-2 E46K-like mutations into the canonical αS repeat motifs (KTKEGV) further reduces tetramers, decreases αS solubility and induces neurotoxicity and round inclusions. The other three fPD missense mutations likewise decrease tetramer:monomer ratios. The destabilization of physiological tetramers by PD-causing missense mutations and the neurotoxicity and inclusions induced by markedly decreasing tetramers suggest that decreased α-helical tetramers and increased unfolded monomers initiate pathogenesis. Tetramer-stabilizing compounds should prevent this

The Trem2 R47H variant confers loss-of-function-like phenotypes in Alzheimer's disease

BACKGROUND: The R47H variant of Triggering Receptor Expressed on Myeloid cells 2 (TREM2) confers greatly increased risk for Alzheimer's disease (AD), reflective of a central role for myeloid cells in neurodegeneration. Understanding how this variant confers AD risk promises to provide important insights into how myeloid cells contribute to AD pathogenesis and progression. METHODS: In order to investigate this mechanism, CRISPR/Cas9 was used to generate a mouse model of AD harboring one copy of the single nucleotide polymorphism (SNP) encoding the R47H variant in murine Trem2. TREM2 expression, myeloid cell responses to amyloid deposition, plaque burden, and neuritic dystrophy were assessed at 4 months of age. RESULTS: AD mice heterozygous for the Trem2 R47H allele exhibited reduced total Trem2 mRNA expression, reduced TREM2 expression around plaques, and reduced association of myeloid cells with plaques. These results were comparable to AD mice lacking one copy of Trem2. AD mice heterozygous for the Trem2 R47H allele also showed reduced myeloid cell responses to amyloid deposition, including a reduction in proliferation and a reduction in CD45 expression around plaques. Expression of the Trem2 R47H variant also reduced dense core plaque number but increased plaque-associated neuritic dystrophy. CONCLUSIONS: These data suggest that the AD-associated TREM2 R47H variant increases risk for AD by conferring a loss of TREM2 function and enhancing neuritic dystrophy around plaques

TREM2 in Neurodegenerative Diseases

Abstract TREM2 variants have been identified as risk factors for Alzheimer’s disease (AD) and other neurodegenerative diseases (NDDs). Because TREM2 encodes a receptor exclusively expressed on immune cells, identification of these variants conclusively demonstrates that the immune response can play an active role in the pathogenesis of NDDs. These TREM2 variants also confer the highest risk for developing Alzheimer’s disease of any risk factor identified in nearly two decades, suggesting that understanding more about TREM2 function could provide key insights into NDD pathology and provide avenues for novel immune-related NDD biomarkers and therapeutics. The expression, signaling and function of TREM2 in NDDs have been extensively investigated in an effort to understand the role of immune function in disease pathogenesis and progression. We provide a comprehensive review of our current understanding of TREM2 biology, including new insights into the regulation of TREM2 expression, and TREM2 signaling and function across NDDs. While many open questions remain, the current body of literature provides clarity on several issues. While it is still often cited that TREM2 expression is decreased by pro-inflammatory stimuli, it is now clear that this is true in vitro, but inflammatory stimuli in vivo almost universally increase TREM2 expression. Likewise, while TREM2 function is classically described as promoting an anti-inflammatory phenotype, more than half of published studies demonstrate a pro-inflammatory role for TREM2, suggesting that its role in inflammation is much more complex. Finally, these components of TREM2 biology are applied to a discussion of how TREM2 impacts NDD pathologies and the latest assessment of how these findings might be applied to immune-directed clinical biomarkers and therapeutics