Mechanisms of Inhibitory Neuron Vulnerability to Alzheimer’s Disease

To understand the mechanisms that control mitochondrial composition and function in fast-spiking parvalbumin-positive interneurons and how these are affected in Alzheimer’s disease.

Inhibitory interneurons, one of the key players in human cognitive processes, are among the first neuronal populations affected by AD onset. I propose their elevated energy consumption rates make these interneurons more vulnerable to AD. Using multiple innovative approaches, I will investigate three fundamental aspects underlying inhibitory interneuron vulnerability to AD. By completing the aims of my proposal, I expect to gain new insights into the pathological basis of this socially devastating neurological condition and contribute to develop novel therapeutic approaches.

The most innovative aspects of my proposal are:

1. The hypothesis: the role of mitochondrial metabolism in fast-spiking PN-INs remains largely unexplored despite extensive knowledge on the functional defects observed in this neuronal subtype at AD onset.
2. The methodology: I will use cutting-edge microscopy and biochemical approaches to probe the functional properties of PV-INs during early stages of AD.
3. The research approach: I will perform all my experiments in vivo using a validated AD mouse model which is significantly more relevant than non-mammalian models or in vitro approaches.

A major challenge in AD research is to identify the initial pathological events that trigger neuronal dysfunction in this neurological disorder. Since PV-IN impairment is one of the earliest abnormalities detected in both patients and animal models of AD, I propose to test whether mitochondrial bioenergetics in PV-INs are affected across disease onset in a well-established AD mouse model. By pursuing these aims, I will provide new insights into the mechanisms underlying PV-IN dysfunction at early stages of AD and identify potential targets for the development of novel therapeutic approaches.