Loss of TREM2 function increases amyloid seeding but reduces plaque-associated ApoE

Abstract

Coding variants in the triggering receptor expressed on myeloid cells 2 (TREM2) are associated with late onset Alzheimer’s disease (AD). We demonstrate that amyloid plaque seeding is increased in the absence of functional Trem2. Increased seeding is accompanied by decreased microglial clustering around newly seeded plaques and reduced plaque associated Apolipoprotein E (ApoE). Reduced ApoE deposition in plaques is also observed in brains of AD patients carrying TREM2 coding variants. Proteomic analyses and microglia depletion experiments revealed microglia as one origin of plaque associated ApoE. Longitudinal amyloid small animal positron emission tomography demonstrates accelerated amyloidogenesis in Trem2 loss of function mutants at early stages, which progressed at a lower rate with aging. These findings suggest that in the absence of functional Trem2 early amyloidogenesis is accelerated due to reduced phagocytic clearance of amyloid seeds despite reduced plaque associated ApoE.

A Consensus Proteomic Analysis of Alzheimer’s Disease Brain and Cerebrospinal Fluid Reveals Early Changes in Energy Metabolism Associated with Microglia and Astrocyte Activation

“…The ability to fully recapitulate the M4 module in AD animal models would help to advance our mechanistic understanding of M4 module relationships with AD neuropathology and cognitive function, and whether it should be targeted for therapeutic reduction or enhancement. Collaborative efforts to generate new AD animal models that better reflect AD pathophysiology are currently underway 90 ; however, recent work on microglial and astrocyte function in current mouse AD models generally supports the findings in this study, and a hypothesis that M4 is associated with a largely protective response 72,84,91,92 .…”

“…Taken together, these findings suggest that lack of an M4 astrocyte/microglial response to plaques in preclinical or clinical AD may lead to more rapid cognitive decline. In this context, it is worth noting that AD risk factor mutations in the microglial TREM2 receptor, which regulates the microglial response to amyloid-β plaques, lead to a reduced microglial response to plaque pathology [83][84][85][86] .…”

Opposite microglial activation stages upon loss of PGRN or TREM 2 result in reduced cerebral glucose metabolism

“…The increased migratory potential is in line with enhanced clustering of IBA1‐positive microglia that we detected around amyloid plaques in APPPS1/ Grn −/− versus APPPS1/ Grn +/+ mice (Figs E and F, and EV1C). Again, this finding is opposite to what was found in the absence of functional TREM2, namely impaired clustering of microglia around amyloid plaques (Wang et al , ; Parhizkar et al , ) and a general reduction of chemotaxis (Mazaheri et al , ).…”

Enhancing protective microglial activities with a dual function TREM 2 antibody to the stalk region

“…We therefore sought a new therapeutic strategy, with the goal to modulate microglial function as a disease‐modifying mechanism. Microgliosis is observed in numerous neurological disorders, and only recently evidence has been presented that TREM2‐dependent microglial functions appear to be protective in AD models (Ulland et al , ; Focke et al , ; Parhizkar et al , ), AD patients (Ewers et al , ), and models of retinal degeneration (O'Koren et al , ). TREM2 plays a central role in the switch of homeostatic to DAM and seems to be acting as a central hub to regulate microglial function (Keren‐Shaul et al , ; Krasemann et al , ; Ulrich et al , ).…”