Understanding the Molecular Mechanisms Underlying Alzheimer’s Disease

BioE Chair and Professor Lee Makowski, in collaboration with Massachusetts General Hospital, received an NIH $2.1M award for “Fibrillar polymorphs in human brain tissue”. Working with neuropathologists from MGH, his research group will be using x-ray scanning microscopy to observe changes in the molecular structure of amyloid plaques and neurofibrillary tangles during disease with the goal of better understanding the molecular mechanisms underlying the disease. Identification of the molecular interactions driving disease should provide clues to aid in the design of therapeutics to slow or halt disease progression.

Alzheimer’s disease is a neurodegenerative disorder in which deposits of abnormal fibrillar aggregates accompany the spread of neuronal damage during disease progression. A central hypothesis of this project is that the role of these fibrillar aggregates may be clarified by observing them in the context of diseased tissue.  To do this, a multidisciplinary team will use methods that generate detailed information on fibril structure and organization while preserving information on their locations across multiple length scales.

Abstract Source: NIH

Fibrillar polymorphs in human brain tissue Project Summary Alzheimer’s disease (AD) is a neurodegenerative disorder defined by the accumulation of protein deposits of Aβ peptide and tau protein. Progression of AD involves spread of tau deposits, called neurofibrillary tangles, along well charted anatomical pathways in the brain. Tauopathies such as Pick’s disease, frontotemporal dementia, progressive supranuclear palsy (and others) are associated with alternate patterns of pathology throughout the brain with the consequent differences in clinical phenotypes. The structures of fibrillar polymorphs of tau have been determined at high resolution and there are well-established differences in the dominant isoform/polymorph of tau associated with each of these diseases. It has been suggested that differences in composition, structure and post-translational modifications (PTMs) of tau oligomers/fibrils among individuals lead to differences in bioactivity that impact disease attributes such as age of onset, rate of progression and anatomical distribution of pathology. In order to test that hypothesis, methods will be used to observe tau in situ, in different brain areas and at different phases of disease. A central hypothesis of this project is that interrogating the structure of tau aggregates in the context of intact tissue during disease progression can clarify if homogeneity or heterogeneity is the predominant feature of tau deposits that contribute to an individual’s Alzheimer phenotype. Advanced techniques will be used to prepare human brain samples and enable scanning x-ray microdiffraction (XMD) to map in situ the distribution of structural variations at the molecular level. Mapping the distribution of fibrillar and non-fibrillar structure within and among tau lesions will provide a measure of the degree to which disease progression is driven by prion-like spreading and clarify the role of non-fibrillar condensates in seed and fibril nucleation. Evolution of the structural organization of lesions will be tracked by studies of different regions of the brain at Braak stage II onward. For each case, independent of disease stage, the entire tau-Braak pathway will be investigated to detect any pre-fibrillar deposits or alterations in tissue structure that may precede or coincide with the emergence of fibrillar pathology. Observations in typical AD cases will be compared with analogous studies of Pick’s disease, progressive supranuclear palsy (PSP), FTLD-Tau (Frontotemporal lobar degeneration with tau pathology with P301L tau mutations) and resilient cases (in which high plaque burden is observed in the absence of overt clinical dementia). This will define the breadth of variation in fibrillar structure and organization in these neuropathies and test the hypothesis that disease-specific polymorphs interact with brain tissue in distinct ways that lead to different anatomical distributions of pathology and variation in disease phenotype. Correlation of observations across brain regions and at various stages of disease will make possible detection of patterns in the molecular structure of plaques and tangles, construction of a sequence of events that may reveal causal relationships and clarify the nature of underlying molecular processes as a basis for identifying molecular interactions essential to disease progression and thereby susceptible to clinical intervention.

Related Faculty: Lee Makowski

Related Departments:Bioengineering