Abstract
Immunotherapeutic approaches are currently the most advanced treatments for Alzheimer's disease (AD). Antibodies against amyloid β‐peptide (Aβ) bind to amyloid plaques and induce their clearance by microglia via Fc receptor‐mediated phagocytosis. Dysfunctions of microglia may play a pivotal role in AD pathogenesis and could result in reduced efficacy of antibody‐mediated Aβ clearance. Recently, heterozygous mutations in the triggering receptor expressed on myeloid cells 2 (TREM2), a microglial gene involved in phagocytosis, were genetically linked to late onset AD. Loss of TREM2 reduces the ability of microglia to engulf Aβ. We have now investigated whether loss of TREM2 affects the efficacy of immunotherapeutic approaches. We show that anti‐Aβ antibodies stimulate Aβ uptake and amyloid plaque clearance in a dose‐dependent manner in the presence or absence of TREM2. However, TREM2‐deficient N9 microglial cell lines, macrophages as well as primary microglia showed significantly reduced uptake of antibody‐bound Aβ and as a consequence reduced clearance of amyloid plaques. Titration experiments revealed that reduced efficacy of amyloid plaque clearance by Trem2 knockout cells can be compensated by elevating the concentration of therapeutic antibodies.
Highlights
Alzheimer’s disease (AD) is the most abundant neurodegenerative disorder and threatens our aging society
We have shown that certain mutations in triggering receptor expressed on myeloid cells 2 (TREM2) such as p.T66M reduce the ability of microglia to phagocytose amyloid b-peptide (Ab) fibers, bacteria, and beads due to impairment of TREM2 maturation and cell surface transport (Kleinberger et al, 2014)
Rare heterozygous mutations in TREM2, which within the brain is exclusively expressed in microglia cells, dramatically increase the risk for late onset AD in a magnitude similar to ApoE e4 (Guerreiro et al, 2013; Jonsson et al, 2013)
Summary
Alzheimer’s disease (AD) is the most abundant neurodegenerative disorder and threatens our aging society. C-Secretase inhibition caused major side effects in a clinical trial, which were at least partially due to inhibition of its biological activity in Notch signaling (Doody et al, 2013). The most advanced and very promising therapeutic approach is currently the anti-Ab immunotherapy (Wisniewski & Goni, 2015), a treatment strategy initiated after the pivotal report by Schenk et al (Schenk et al, 1999) demonstrating its efficacy in amyloid plaque removal and reduction in memory decline in an animal model (Morgan et al, 2000). Initially there was no obvious beneficial effect on memory, data from two recent clinical trials suggest that immunotherapy may significantly slow memory decline (Reardon, 2015). A recent clinical trial using Aducanumab indicated that significant amyloid removal is required for clinical benefits suggesting a critical role of amyloid removal by microglia.
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