Alzheimer’s disease (AD) is the most common form of dementia characterized by neuronal loss and synaptic
dysfunction, and histopathologically hallmarked by the presence of amyloid plaques and neurofibrillary tangles.
The correlation between histopathology and dementia has been challenged in the past decade by the emergence
of a group of individuals who remain cognitively intact despite the presence of plaques and tangles consistent
with clinically symptomatic AD. The existence of these individuals, here referred to as Non-Demented with AD
Neuropathology (NDAN) suggests that there is a natural way for the human brain to escape dementia.
Understanding the underlying molecular and cellular mechanisms of resilience (the main objective of the present
project) may help the development of innovative treatment concepts based on inducing cognitive resilience in
anyone challenged by AD neuropathology.
We present compelling preliminary results that support our hypothesis that efficient TREM2-driven microglial
phagocytosis underlies structural integrity and functionality of synapses in NDAN, thus protecting from
ensuing cognitive deficits. We will test our central hypothesis by pursuing the following specific aims: testing
whether high expression levels of microglial TREM2 are associated with phagocytosis of damaged
synapses around amyloid plaques in NDAN subjects, and evaluating the presence of variants of
TREM2 gene in NDAN subjects as a function of synaptic resilience.
This present project is highly significant because the proposed studies will establish TREM2 phagocytic microglia
as a key player in the maintenance of synaptic integrity. The successful completion of the aims will provide
insight into molecular and cellular mechanisms underlying synaptic resilience in relation to microglia activity in
NDAN individuals revealing new targets for future development of innovative treatment concepts based on
inducing cognitive resilience in individuals challenged by AD neuropathology. The proposed project will improve
our scientific understanding of how damaged synapses removal is mediated by TREM2 phagocytic microglia
contributing to synaptic integrity in NDAN.