2023 Alzheimer's Association Research Fellowship (AARF)
Understanding Synapse Mechanism Underlying Resilience to Alzheimer Disease
Can tau protein promote memory loss in Alzheimer’s by damaging structures important for brain cell communication?
Sunny Kumar, Ph.D.
Massachusetts General Hospital
Charlestown, MA - United States
Background
In Alzheimer’s and other brain diseases, the shape of tau protein becomes modified or “misfolded,” a process involving the addition of phosphate molecules to the tau protein. This form of tau, referred to as phosphate tau or ptau, can form clumps called “oligomers,” which contain only a few tau molecules and often develop early on in Alzheimer’s. Tau oligomers have been shown to damage brain cells in the disease and promote memory loss and other forms of cognitive decline.
Current research indicates that the ability of tau oligomers to damage brain cells may involve synapses (the specialized structures through which nerve cells communicate with each other). Dr. Sunny Kumar and colleagues, for example, have studied individuals with a “resilient” form of Alzheimer’s – that is, people who have high brain levels of ptau and beta-amyloid (another Alzheimer’s-related protein) but do not develop cognitive decline. The researchers found that these individuals have lower levels of ptau in their synapses, which suggests resilient Alzheimer’s may protect cognitive health by preventing tau-related synaptic damage. Moreover, according to other studies, people with resilient Alzheimer’s may also experience less synaptic damage from “helper” cells called glial cells. Glial cells normally support synaptic function, in part, by “pruning” (or removing) damaged or unwanted synapses. But when tau oligomers develop in glial cells during early Alzheimer’s, this pruning action may become excessive, leading to the removal of healthy synapses and, ultimately, cognitive decline. This disease process appears to be reduced in people with resilient Alzheimer’s.
Research Plan
Dr. Kumar and colleagues will examine how tau oligomers and glial cells impact synapses and cognitive health in different forms of Alzheimer’s. They will examine brain tissue from individuals who had resilient Alzheimer’s or “demented” Alzheimer’s (Alzheimer’s with cognitive loss). First, they will confirm whether ptau levels were lower in resilient Alzheimer’s brains, compared with demented Alzheimer’s brains; and whether the reduced ptau resulted in higher levels of preserved synapses. They will then assess whether resilient Alzheimer’s brains had fewer synapses “engulfed” (or removed) by glial cells than did demented Alzheimer’s brains, and determine the role of ptau oligomers in this synapse removal process.
Impact
Dr. Kumar’s study could shed new light on the molecular mechanisms underlying cognitive decline in Alzheimer’s. It could also lead to novel dementia therapies for preventing tau-related synaptic damage.