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).
Alzheimer’s disease (AD) research is entering the exciting phase in which the hard won knowledge about the molecular basis of this disorder is being translated into therapeutics. However, recent drug trials have highlighted a need for a better understand of the molecular pathology of AD and for accurate diagnosis of trial participants. Consequently most of our work focuses on better understanding the molecular identity of the most disease relevant forms of Aß and tau. These includes non-classical forms of Aß such as N-terminally extended Aß species, fragments bearing all or part of the Aß sequence, APP fragments and interactions between Aß and APP. With regards to tau we recently reported that tau is released by mechanisms both dependent on and independent of cell death and that the bulk of the released protein is C-terminally truncated. Interestingly, the region involved in tau aggregation, the so-called micro-tubule binding region (MTBR), lies within the C-terminus of tau, thus the major form(s) of tau released by cells does not contain the aggregation-prone MTBR. Separately, we and others have shown that most tau in human CSF is also C-terminally truncated, and that treatment of an AD mouse model with an antibody to the mid-region of tau causes seizures and death. These results lead us to hypothesize: (i) that extracellular C-terminally truncated tau (eTauΔC) has a physiologic role and that inappropriate targeting of this form of tau will have deleterious effects, and (ii) measurement of C-terminal-containing tau (eTau+C) should prove useful for diagnosis of AD. By understanding the complexity of the various forms of Aß, APP and tau we hope to gain insight on the molecular pathogenesis of AD and to identify specific forms of these proteins that can be measured in human fluids and used as biomarkers of disease.
Current Funded Research
National Institute of Health, R01-AG046275 (Walsh, PI)
Water-soluble Aβ and its role in Alzheimer’s disease
The primary goals of this project are to identify from human brain toxic forms of Aß, to use this information to rigorously test fundamental unresolved questions about Aß’s role in AD, and to determine whether antibodies that specifically target toxic forms of Aß have therapeutic potential.
Alzheimer’s Drug Discovery Foundation (Walsh, PI)
Neurally-derived exosomes for the diagnosis and staging of sporadic Alzheimer’s Disease.
There is an urgent need for blood-based test for AD. But the contents of blood are influenced by many organs and therefore changes in blood might not be sensitive to minor changes in brain that occur early in AD. Extracellular vesicles can pass from the brain into the blood and therefore provide a unique opportunity to detect changes occurring in the brain. We propose to isolate extracellular vesicles from blood and analyze their tau and Ab levels.
Med Immune, Inc. (Walsh, PI)
Understanding the protective effects of MEDI1814:
The goal of this project is to determine if the investigational anti-Aβ antibody, MEDI 1814, can engage with Ab oligomers and alter tau alloforms in human biofluids.
Harvard Center for Neurodiscovery (Walsh, PI)
Deep phenotyping: a longitudinal Alzheimer’s biomarker program
The primary goal of this project is to use highly sensitive technologies to identify and measure the levels of novel Aβ and tau biomarkers in human fluids.
The Binational Science Foundation Grant ID: 2013244 (Walsh, PI)
US – Israel Binational Science Foundation
Targeting Aß induced hippocampal hyperactivity via APP homodimers
The goal of this project is to shed light on the molecular mechanisms initiating synaptic hyperactivity and cognitive deficits at very early stages of AD, providing new strategies for preventing memory decline in AD patients.
National Institutes of Health, R21-AG047505 (Walsh, PI)
Exploiting PrP for the diagnosis and treatment of protein aggregation diseases.
The overall goal of this proposal is to exploit the finding that the prion protein (PrP) can recognize certain disease-causing aggregates and to use PrP to guide the generation of new tools for the detection and treatment of aggregate-induced neurodegeneration.
Marr Alzheimer Fund (Walsh, PI)
Brain-derived exosomes in blood – a window on the brain in blood.
The goal is to isolate brain-derived exosomes from human plasma and iPSC-derived neurons and to measure the levels and forms of Aß and tau both inside and on the surface of exosomes.
Sanofi Inc. (Walsh, PI)
Monoclonal antibodies neutralizing AD-brain derived synaptotoxic Aß assemblies
Use novel B-cell cloning technology to isolate human mAßs that recognize toxic forms of Aß and further optimized identified IgGs to reverse Aß synaptotoxicity and minimize off-target engagement.