Dementia with Lewy bodies (DLB) and Parkinson's disease dementia (PDD), collectively called Lewy body dementias (LBDs), are the second most common cognitive disorder after Alzheimer's disease (AD). Patients with LBDs suffer from PD-related motor defects and deficits in executive dysfunction, attention, and visuospatial processing, reflective of cortical dysfunction. Pathologically, LBDs are characterized by abundant cortical aggregates of ?-synuclein (?-syn) called Lewy pathology (LP). The cognitive impairments in LBDs are the main cause for institutionalization and mortality. There are no treatments that halt the progression of LBDs. Outstanding scientists in the field of LBDs have provided data supporting that the combination of Lewy pathology and aggregates of tau, similar to those found in Alzheimer's disease, together are strongly associated with reduced performance on cognitive tasks. In Alzheimer's disease, loss of synapses is the strongest correlate of cognitive decline. Recently evidence has emerged from several labs, including ours,that synapse loss in the cortex may contribute to cognitive changes in LBDs. We propose that the presence of both alpha-synuclein and tau aggregates at the synapse synergistically contributes to synapse degeneration in LBDs. We propose the interaction of ?-syn and tau at the presynaptic terminal induces synapse degeneration. This proposal will combine the expertise of multiple investigators to test whether 1) the interaction of alpha- synuclein and tau facilitates synapse degeneration and 2) whether presynaptic terminals with small aggregates of both alpha-synuclein and tau show enhanced degeneration in the prefrontal cortex of patients that suffered from Lewy body dementias. We will use novel antibodies that selectively detect oligomeric and pathologic conformation of alpha-synuclein and tau. We will use a novel super-resolution technique called Expansion Microscopy (ExM) that can rapidly and quantitatively provide nanoscale resolution of synapses. We will also use a novel antibody multiplexing technique that can amplify low-abundance synaptic signals and allow imaging of >5 proteins at once. The results of this proposal will move the field of LBDs forward by 1) beginning to elucidate the mechanisms that contribute to synapse loss and cognitive changes in LBDs, and 2) identify if targeting the alpha-synuclein/tau interaction prevents synapse loss and cognitive decline.

Public Health Relevance

Clumps of a protein in the brain called Lewy pathology are found in the brains of patients who suffered from Parkinson's Disease and Dementia with Lewy Bodies. This proposal will determine how these protein aggregates disrupt communication among neurons in the brain, particularly in a brain area called the cortex which is important for cognition. Our goal is to discover novel therapeutic targets to prevent cognitive changes in these neurodegenerative diseases.

National Institute of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
High Priority, Short Term Project Award (R56)
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Cellular and Molecular Biology of Neurodegeneration Study Section (CMND)
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Sieber, Beth-Anne
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University of Alabama Birmingham
Schools of Medicine
United States
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