Soluble TREM2 ameliorates pathological phenotypes by modulating microglial functions in an Alzheimer’s disease model

Abstract

Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglial surface receptor genetically linked to the risk for Alzheimer’s disease (AD). A proteolytic product, soluble TREM2 (sTREM2), is abundant in the cerebrospinal fluid and its levels positively correlate with neuronal injury markers. To gain insights into the pathological roles of sTREM2, we studied sTREM2 in the brain of 5xFAD mice, a model of AD, by direct stereotaxic injection of recombinant sTREM2 protein or by adeno-associated virus (AAV)-mediated expression. We found that sTREM2 reduces amyloid plaque load and rescues functional deficits of spatial memory and long-term potentiation. Importantly, sTREM2 enhances microglial proliferation, migration, clustering in the vicinity of amyloid plaques and the uptake and degradation of Aβ. Depletion of microglia abolishes the neuroprotective effects of sTREM2. Our study demonstrates a protective role of sTREM2 against amyloid pathology and related toxicity and suggests that increasing sTREM2 can be explored for AD therapy.

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

“…Additional data will also be required to demonstrate that antibodies with properties similar to 4D9 can be used to modulate microglial function for the treatment of AD or other indications. In that regard, it is currently unclear whether sTREM2 itself may have essential functions in either a cell‐autonomous manner or a non‐cell‐autonomous manner (Ulland et al , ; Zhong et al , , ). Moreover, although a loss of function as caused by certain risk variants of TREM2 disables microglia, relegating them to a homeostatic state (Mazaheri et al , ), absence of progranulin (PGRN) has the opposite consequence, namely arresting microglia in a disease‐associated state (Gotzl et al , ).…”

“…Full‐length TREM2, in association with DAP12, forms a heteromeric complex required to activate phospho‐SYK signaling (Colonna, ). Signaling appears to be terminated by α‐secretase‐mediated shedding of the TREM2 ectodomain (Fig A) (Wunderlich et al , ; Kleinberger et al , ), although very recent data suggest that soluble TREM2 (sTREM2) may also have signaling functions (Zhong et al , , ), and requires further investigation. Loss of TREM2‐mediated signaling locks microglia in a homeostatic state and inhibits their transition to disease‐associated microglia (DAM) (Krasemann et al , ; Mazaheri et al , ), which are phenotypically characterized by enhanced migration, chemotaxis, and phagocytosis (Keren‐Shaul et al , ; Mazaheri et al , ).…”

Inhibition of REV‐ERBs stimulates microglial amyloid‐beta clearance and reduces amyloid plaque deposition in the 5XFAD mouse model of Alzheimer’s disease

“…We suspect that REV‐ERBs activity might participate in LANDO via modulating the expression of receptors in microglia. TREM2 is a well‐characterized Aβ receptor that participates in Aβ endocytosis and elimination and can help glia‐mediated synaptic engulfment in neurodevelopment (Jay et al, ; Zhong et al, ). Interestingly, SR8278 significantly increased the expression of DAP12 which is considered as TREM2 adaptor in microglia, as well as induced TREM2 levels, indicating that SR8278 could propagate TREM2 downstream signaling in microglia.…”

Functional insights from biophysical study of TREM2 interactions with ApoE and Aβ1-42

“…For example, elevated levels of sTREM2 are associated with cognitive reserve in humans [10], and increasing sTREM2 in a mouse model of AD ameliorates disease pathologies, including reducing amyloid plaque load and improving functional memory [11]. Aside from modulating the function of receptor TREM2, sTREM2 could have independent functions as a cytokine-like signaling molecule [12,13] or function in some other capacities.…”