Author interview — Prateek Kumar is a research scientist at Yale University. He uses multi-omics-based approaches to investigate mechanisms of neurodegeneration in Alzheimer’s disease to find novel therapeutic strategies.
We used a new approach to label proteins in a group of neurons called parvalbumin-positive interneurons in the mouse brain and used proteomics to understand why these neurons are vulnerable in early stages of Alzheimer’s pathology.
By applying proteomic and electrophysiological approaches to study PV-INs in the brain of mice with early AD pathology, we have obtained novel and therapeutically-relevant insights into early mechanisms of neuronal vulnerability in AD.
The brain is composed of billions of neurons and other cell types. Parvalbumin-positive interneurons (PV-IN), a type of inhibitory neuron, primarily function to regulate the activity of other neurons, ensuring that brain signals remain balanced and properly synchronized. These PV-INs appear to be uniquely vulnerable in Alzheimer’s disease (AD) but the mechanisms for this are unknown. It is important to understand the basis for PV-IN vulnerability in AD to develop new therapeutic approaches to treat AD. To answer this question, we used our recently developed mouse model system which can uniquely label the proteins of a cell type of interest in their native state, so that we can use mass spectrometry to measure thousands of proteins (the proteome) within PV-INs, and examine how these change at early stages of AD. One of the major findings in this study is that at the early stages of AD, PV-INs are prone to developing synaptic and metabolic defects, which corresponds to decreased neurotransmission. The proteins that decrease in PV-INs include proteins that are responsible for cognitive resilience in humans, suggesting that the early changes we discovered in PV-INs are very likely to cause synaptic and cognitive problems. By examining the native-state proteome of PV interneurons, we provide evidence supporting the potential for early targeting of these interneurons in AD.
Reference: P Kumar., et al. Native-state proteomics of Parvalbumin interneurons identifies unique molecular signatures and vulnerabilities to early Alzheimer’s pathology. Nature Communication 15, 2823 (2024).
