TREM2 modulates differential deposition of modified and non-modified Aβ species in extracellular plaques and intraneuronal deposits

Abstract

Progressive accumulation of Amyloid-β (Aβ) deposits in the brain is a characteristic neuropathological hallmark of Alzheimer’s disease (AD). During disease progression, extracellular Aβ plaques undergo specific changes in their composition by the sequential deposition of different modified Aβ species. Microglia are implicated in the restriction of amyloid deposits and play a major role in internalization and degradation of Aβ. Recent studies showed that rare variants of the Triggering Receptor Expressed on Myeloid cells 2 (TREM2) are associated with an increased risk for AD. Post-translational modifications of Aβ could modulate the interaction with TREM2, and the uptake by microglia. Here, we demonstrate that genetic deletion of TREM2 or expression of a disease associated TREM2 variant in mice lead to differential accumulation of modified and non-modified Aβ species in extracellular plaques and intraneuronal deposits. Human brains with rare TREM2 AD risk variants also showed altered deposition of modified Aβ species in the different brain lesions as compared to cases with the common variant of TREM2. These findings indicate that TREM2 plays a critical role in the development and the composition of Aβ deposits, not only in extracellular plaques, but also intraneuronally, that both could contribute to the pathogenesis of AD.

Microglia and Neuroinflammation: Crucial Pathological Mechanisms in Traumatic Brain Injury-Induced Neurodegeneration

“…In neurodegenerative diseases such as AD, multiple TREM2 variants in microglia have also been reported from human data to play a role, loss-of-function of which is closely link to elevated risk of developing the disorders (Guerreiro et al, 2013;Ulland and Colonna, 2018). Furthermore, recent study revealed that genetic knockout of TREM2 in mice regulates deposition of Aβ species in extracellular plaques, as well as intraneuronally, in line with the findings from AD patients (Joshi et al, 2021).…”

Mechanisms contributing to differential genetic risks for TREM2 R47H and R62H variants in Alzheimer’s Disease

“…Fewer studies of the impact of these variants in human tissue have been reported. These have either not shown differences or have reported increased amyloid load and glial inflammatory activation with TREM2var relative to CV [15][16][17][18] . Neuronal tau pathology with TREM2 R47H and R62H was reported to show no change 15,16 or a decrease 17 relative to CV.…”

APOE and immunity: Research highlights

“…Evidence that TREM2 plays a role in supporting the compaction of amyloid plaques and the clustering of microglia around amyloid plaques, which in turn helps to reduce plaque‐associated neuritic pathology, 106,108,109 suggests that TREM2 agonist antibodies might be used to successfully target amyloid accumulation. Indeed, the AL002c and 4D9 antibodies have been tested to determine whether they affect amyloid accumulation in the brain of transgenic AD mouse models 105,107,110 .…”

“…Moreover, all of these antibodies are characterized by dual mechanisms of action, such that each is capable of promoting TREM2 signaling by means of the cross-linking of surface TREM2, which stimulates phagocytosis and the removal of cellular debris, and also is capable of inhibiting TREM2 shedding. 106,107 Evidence that TREM2 plays a role in supporting the compaction of amyloid plaques and the clustering of microglia around amyloid plaques, which in turn helps to reduce plaque-associated neuritic pathology, 106,108,109 suggests that TREM2 agonist antibodies might be used to successfully target amyloid accumulation. Indeed, the AL002c and 4D9 antibodies have been tested to determine whether they affect amyloid accumulation in the brain of transgenic AD mouse models.…”