Research

Autophagy in Synaptic Homeostasis and Cognition

Autophagy is a critical homeostatic pathway within the cell, yet when we deactivate it in adult mice, there is a not a catastrophic failure of cellular function. Rather, compensatory mechanisms kick in and the animals continue to function relatively normally. However, we have found that the synapse is uniquely reliant upon autophagy for synaptic protein homeostasis. In parallel, we identified a time-dependent decline in cognitive function after autophagy deactivation. The goal of this project is to establish a causative link between the loss of synaptic protein homeostasis and impaired cognitive function in the absence of functional autophagy.

Autophagy in Normal Cognitive Aging

Normal aging is associated with a decline in cognitive function, which is referred to as “normal cognitive aging.” Autophagic function also declines with age, yet its importance to the synapse rises over the lifespan. The goal of this project is to determine how autophagic processing of synaptic proteins changes with age, and whether enhancing autophagic clearance of synaptic cargo can protect against this normal cognitive aging. *This work is funded in part by The Glenn Foundation for Medical Research and AFAR Grant for Junior Faculty.

The Impact of Alzheimer's Disease Associated Pathology on Autophagic Function

Autophagy has long been implicated in the pathophysiology of Alzheimer's disease, images/Labs/Grosso Lab/Grosso lab research page image 3a.png but many questions remain unanswered regarding when during the disease process autophagy becomes disrupted, how Alzheimer’s disease pathophysiology impacts autophagic function, and how, in turn, disruption of autophagy contributes to further degeneration. This project utilizes a mouse model of Alzheimer’s disease and cell cultures derived from that model organism to investigate images/Labs/Grosso Lab/Grosso lab research page image 3b.png these questions. *This work funded in part by The Busch Biomedical Research Grant.

Region-specific reliance upon autophagy

One particularly enigmatic aspect of neurodegenerative diseases is the early regional vulnerability. We have found differences in how various brain regions utilize autophagy. The goal of this project is to better characterize these regional differences and to investigate if the differential reliance on autophagy may contribute to the regional vulnerability seen in neurodegenerative diseases.

The Mechanistic Role of Autophagy in Synapses

Disruption of autophagy interferes with synaptic function, and synaptic activity upregulates autophagic activity. Therefore, it has often been assumed that autophagy actively participates in the response of the synapse to a signal, for example, by participating in synaptic vesicle (SV) release in response to an action potential or removing neurotransmitter receptors from the post-synaptic membrane in response to signals to decrease synaptic strength. However, autophagy also has basal activity in synapses, suggesting that it is necessary for synapse homeostasis as well. Disruption of this function could alone be sufficient to explain the synaptic alterations that follow autophagy impairment. The goal of this project is to use live-cell imaging of autophagy deactivated cells to differentiate between these possibilities.