Detection and Characterization of Alpha-Synuclein Aggregates in Patients with Alzheimer s Disease and Related Dementia
Abstract
Dementia is currently the seventh leading cause of death. Around 55 million people have dementia worldwide and that number is expected to rise to 78 million by 2030 and 139 million by 2050. Alzheimer s disease (AD) is the most common form of dementia, contributing to two-thirds of dementia cases and affecting more than 5 million people in the Unites States. Other forms of dementia include vascular dementia (VaD), frontotemporal dementia (FTD), and Lewy body dementia (LBD). LBD includes dementia with Lewy bodies (DLB) and Parkinson s disease dementia (PDD). AD and related dementias (ADRD) are associated with abnormal buildups of proteins in the brain causing nerve cells or neurons to stop working properly and eventually die. In AD, abnormal deposits are in the form of amyloid plaques and neurofibrillary tangles composed of amyloid-beta and hyperphosphorylated Tau. DLB and PDD are associated with abnormal clumps of a protein called alpha-synuclein in the neurons in the form of Lewy bodies and Lewy neurites. Despite this, it is common to find a substantial overlap of pathological abnormalities in different patients, leading to the relatively frequent appearance of mixed pathologies, characterized by the presence of abnormal deposits composed of multiple proteins in the same brain. Indeed, up to 30%-40% of AD patients display abnormal alpha-synuclein deposits in their brains. Although much research has focused on abnormal amyloid-beta and hyperphosphorylated Tau in AD, little is known about the characteristics of alpha-synuclein in AD and related dementias. Here we hypothesize that the detection of abnormal alpha-synuclein protein in biological fluids may differentiate LBD patients from other forms of dementia and help to identify subset of AD cases that have alpha-synuclein deposits in their brains. We also hypothesize that abnormal alpha-synuclein proteins implicated in different diseases may have different characteristics that affect different cell types in the brain. Recently, we have developed a highly sensitive and specific assay Protein Misfolding Cyclic Amplification assay to detect abnormal alpha-synuclein (termed alpha-synuclein-PMCA) in biological fluids of patients affected by Parkinson s disease (PD) and other synucleinopathies. The major goal of this project is to elucidate the contribution of alpha-synuclein in dementias by developing and validating a test to detect abnormal alpha-synuclein in biological fluids of patients affected by AD, LBD and other dementias. The detection of abnormal alpha-synuclein in biological fluids may serve to recognize LBD patients from other forms of dementia and to identify subset of AD cases. Furthermore, we will characterize these abnormal alpha-synuclein amplified from biological fluids, brain tissue and distinct cell types using variety of biochemical and structural techniques including high-resolution atomic structure using cryo-electron microscopy (cryo-EM). Finally, we will analyze the biological properties of abnormal alpha- synuclein amplified from biological samples of patients affected by diverse dementias in vitro and in vivo using cellular and transgenic animal models. The findings obtained here will enable researchers to identify LBD and subset of AD patients with abnormal alpha-synuclein deposits in the brain and might have tremendous impact on designing therapeutic intervention to eliminate abnormal alpha-synuclein protein in combination with abnormal amyloid beta and tau proteins in this subset of AD patients. Finally, this study will provide in-depth characteristics of abnormal alpha-synuclein deposited in AD and LBD brains.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310929
Entities
People
- Mohammad Shahnawaz
Organizations
- United States Army
- University of Texas Health Science Center at Houston