Walsh Laboratory – Brigham and Women's Hospital

We are striving to develop a knowledge base that will allow the development of rationally designed drugs to slow or halt Alzheimer’s disease (AD).

Research Narrative:

Extracellular fibrous amyloid deposits or intracellular inclusion bodies containing abnormal protein fibrils characterize many neurodegenerative disorders, including Alzheimer’s disease. The burden of evidence suggests that the accumulation of protein aggregates plays a seminal role in pathogenesis. We have been at the forefront of studies on the role of soluble Aß oligomers in AD and are committed to understanding the mechanisms of Aß toxicity and the structure of noxious Aß assemblies. We are also actively investigating the involvement of the prion protein in AD and how Aß causes changes in tau metabolism. In particular, we are excited by emerging data that suggest certain forms of tau are secreted from neurons by unconventional mechanisms and that this may contribute to the stereotypic spread of tangle pathology in AD. This work has the potential not only to identify new drug targets for the treatment of AD, but also to identify novel biomarkers.

Different Aß assembly forms may mediate diverse cytotoxic effects, including decreased synaptic efficacy, distortion of axonal pathways, shrinkage of dendritic arbors, activation of microglia, free radical release, and inflammatory changes. This cartoon depicts the distortion of axonal trajectories observed within amyloid plaques and the periplaque activation of (1) astrocytes, resulting in the release of various cytokines (Ck) and (2) microglia, resulting in the generation of superoxide radicals (O2-). Disruption of synaptic efficacy by diffusible, low-n oligomers of Aß is depicted as a decrease in normal transmission at synapses (green cloud) due to the presence of forms of Aß that can diffuse into the cleft that can contact synaptic plasma membranes. All Aß species are shown in red, with amyloid plaques shown as an interwoven mass of fibrils and soluble Aß depicted as stacked W-shaped structures (suggesting their ß-sheet-rich structure).

For these projects we apply a wide range of advanced biochemical, molecular, cell biological, electrophysiological and behavioural methods. Our work is currently supported by the NIH (USA), Alzheimer Drug Discovery Foundation, MedImmune, Harvard NeuroDiscovery, the Binational Science Foundation, the SENS foundation, the Wolfson Foundation, the Thysson Krupp Foundation, Sanofi, and by philanthropic donations.

Research Narrative:

Alzheimer’s Association Zenith Award

Dr. Walsh becomes first head of ADRU

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