Heterogeneity in toxicity of oligomeric amyloid beta and neuronal resilience in Alzheimer disease

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PROJECT SUMMARY This proposal presents a five-year research and career development plan for Andrew Stern, MD, PhD, in the molecular basis of Alzheimer disease (AD), the leading cause of age-related cognitive failure worldwide. Dr. Stern is an Instructor in cognitive and behavioral neurology at Brigham and Women’s Hospital (BWH). The “amyloid cascade hypothesis” is the most studied theory of AD pathogenesis, positing that abnormalities in the metabolism of the Aβ peptide lead to the two defining pathologic lesions of AD (amyloid plaques of aggregated Aβ and neurofibrillary tangles of hyperphosphorylated tau), followed by loss of neurons. There are two central problems with this hypothesis: some patients have abundant amyloid plaques but little neuronal and cognitive loss; and clinical trials of antibodies that removed amyloid plaques have largely failed to slow decline. This proposal addresses these problems by beginning two answer two questions: 1) What biochemical and structural characteristics of the most toxic form of Aβ, soluble oligomers (oAβ), confer its toxicity? Novel monoclonal antibodies will be used to test if calcium-associated and low molecular weight oAβ subsets are correlated with tau abnormalities and dementia. CryoEM will allow structural characterization of immunoaffinity purified calcium-associated oAβ. 2) Do genetic differences cause some patients’ neurons to be more susceptible to toxic oAβ, and is oAβ from patients with high tau burden and dementia more toxic than oAβ from patients without? Induced pluripotent stem cell-derived neurons (iNs) and post mortem brain tissue, from patients with high amyloid pathology but varying tau and cognitive impairment will be compared using live cell imaging. An important innovation is to use naturally-occurring, human brain-derived oAβ, which may be more disease-relevant than synthetic oAβ. These experiments will help explain inconsistencies in our models of AD pathogenesis. In the long term, the results may assist clinical trial and drug design. The training goals of this proposal are for Dr. Stern to develop the necessary expertise to establish an independent laboratory researching the molecular pathogenesis of AD under R01 funding. Over the five years, Dr. Stern will acquire specific skills each with the one-on-one mentorship of an expert advisor: Aβ biochemistry (Dr. Selkoe), iN models (Dr. Young-Pearse), protein conformational chemistry and structural biology (Dr. Vos), neuropathology of neurodegeneration (Dr. Feany), and knowledge of AD clinical therapeutic development (Dr. Sperling). Dr. Stern has developed a training plan consisting of one-on-one meetings, in-person courses, and conferences. All mentors and advisors are renowned experts in their fields. Dr. Selkoe (primary mentor) is a leading AD researcher with decades of mentorship experience, including successful K08 awardees. Dr. Young- Pearse (co-mentor) is also a leading AD researcher, particularly in iN models of disease, and an accomplished mentor. The BWH Department of Neurology is committed to supporting Dr. Stern through protected research time (85%) and state-of-the-art facilities and equipment.