TDP-43 in the Aging Brain: When and Where?

The presence of TDP-43 protein aggregates is linked to a faster decline in Alzheimer’s patients. We will assess a large collection of human brains for TDP-43 and isolate the most affected cells.

Diseases of the aging brain, such as Alzheimer’s, are caused by multiple factors, including the proteins amyloid and tau, but recently, an additional protein, TDP-43, has been linked to a faster decline in some patients.

We will investigate TDP-43 in a set of autopsied brains from multiple diseases and associate its presence with the presence of amyloid and tau.

We will then study which specific brain cells contain changes in TDP-43 levels and what that does to them, which could help to understand how TDP-43 relates to aging and dementia.

Our proposal applies state-of-the-art computer vision and machine learning techniques to more accurately characterize the burden of TDP-43 pathology in the aging and Alzheimer’s brain.

Secondly, the cell types and subtypes most affected by TDP-43 pathology are unknown. For the first time we will identify TDP-43 pathology-burdened cells by their gene profiles.

Personalized medicine for neurodegeneration aims to identify specific subtypes of disease to develop targeted therapies, analogous to the rapid progress in the cancer field. By dissecting the contribution of TDP-43 to Alzheimer’s and aging, we are laying the groundwork for molecularly targeted therapies.