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TREM2 dependent microglial function and dysfunction: A target for therapeutic modulation of Alzheimer's disease and Frontotemporal Dementia

Subject Area Molecular and Cellular Neurology and Neuropathology
Term from 2018 to 2024
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 394585134
 
Final Report Year 2024

Final Report Abstract

Alzheimer’s disease (AD) and related neurodegenerative disorders pose a major threat to our aging society. Over the past decades, my research has focused on the generation of amyloid β-peptide (Aβ), the primary component of the amyloid plaques that characterize AD. Evidence from genetically inherited AD has strongly supported the amyloid cascade hypothesis, which posits that extracellular Aβ initiates a destructive sequence: it forms neurotoxic Aβ aggregates, which precipitate into amyloid plaques and trigger the formation of intracellular tau aggregates that eventually spread throughout the brain, leading to widespread neuronal death. All known AD-causing mutations in three distinct genes accelerate either the production or precipitation of Aβ, thereby activating the amyloid cascade. Additionally, a protective mutation in the amyloid precursor protein (APP) gene reduces Aβ production by 20– 30% over a lifetime. This genetic evidence overwhelmingly points to a central role of Aβ in AD pathogenesis. Despite this, a critical aspect of AD has remained poorly understood. In all cases of AD, activation of microglia—the brain's immune cells—is observed. This immune response has generally been viewed as contributing to or even causing neurotoxicity. However, while investigating genetic risk factors for late-onset AD (which are exclusively expressed in microglia), we made a surprising discovery: these variants actually impair protective functions of microglia. One such gene, TREM2, acts as a central switch enabling microglia to mount a defensive response against pathological challenges, such as amyloid plaques. Building on this finding, we developed tools to stimulate the TREM2 switch, thereby enhancing the protective response of microglia. In AD mouse models, this approach reduced amyloid plaque accumulation. Furthermore, in human AD patients, high TREM2 activity was shown to be protective: elevated TREM2 levels in early, asymptomatic stages of AD correlate with reduced brain shrinkage and slower cognitive decline. Our preclinical research has also allowed us to identify an optimal therapeutic window for treatment. Denali Therapeutics, our collaborative partner, is now testing this TREM2-targeting approach in clinical trials. In collaboration with research teams in the U.S., France, and the German Center for Neurodegenerative Diseases (DZNE), we have also demonstrated that our TREM2-activating tool has protective effects beyond AD, showing efficacy in models of retinal degeneration, atherosclerosis, obesity, and multiple sclerosis-like syndromes.

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