Human neurons derived from patient skin fibroblasts are used as a model system to investigate the key proteins involved in Lewy body dementia. Advancing research on a common form of dementia

Mayo Clinic researchers have assembled a team of international experts to investigate key proteins involved in Lewy body dementia.

Lewy Body Dementia Center Without Walls

Investigators from Mayo Clinic's Florida campus are leading a Lewy Body Dementia Center Without Walls research initiative funded by a National Institutes of Health (NIH) specialized center-cooperative agreement grant (U54). The overall goal of the Lewy body dementia multi-institutional Center Without Walls (CWOW) initiative is to deepen the understanding of how the Alzheimer's disease-related protein, amyloid-beta, and the Parkinson's disease-related protein, alpha-synuclein, interact to affect symptom presentation, disease progression and the underlying disease process in Lewy body dementia (LBD).

As part of the effort, entitled Synergistic Interactions of Alpha-Synuclein and Amyloid-Beta Species in Lewy Body Dementia, CWOW researchers seek to elucidate novel molecular contributions of alpha-synuclein (α-syn) and amyloid-beta (Aβ) species to neurotoxicity in LBD with the goal of providing unique insight into disease mechanisms with consideration of apolipoprotein E alleles and other genetic factors as modifiers of LBD risk and modulators of pathobiology. Understanding these factors will facilitate further research efforts, the development of diagnostics and future drug discovery work.

Questions addressed by the grant award include:

  • What are the unique structural characteristics of pathogenic α-syn and Aβ in LBD?
  • Do toxic subspecies of α-syn and Aβ interact to promote or accelerate neurotoxicity in LBD?
  • How are α-syn and Aβ processed in neurons within the same LBD brain tissue?
  • How do genetic, lipidomic and proteomic factors contribute to pathogenesis of LBD?

Overall aims

The complementary and synergistic expertise of CWOW investigators addresses critical research questions in LBD research and aims to do the following:

  1. Provide critical resource support to advance the research efforts of this LBD CWOW in the form of a dedicated neuropathology core with standardized approaches to clinical, genetic and neuropathologic characterization of LBD samples shared with the CWOW investigators.
  2. Identify dysfunctional networks, pathways and proteins contributing to synergistic interactions of α-syn and Aβ in LBD using a combination of omics approaches, genetics and pathway or network analyses.
  3. Discover the unique structural characteristics of α-syn and Aβ subspecies in LBD.
  4. Determine the contribution of genetic factors to disease pathogenesis and neurotoxicity of α-syn and Aβ in LBD.
  5. Evaluate mechanisms of synergistic interactions of α-syn and Aβ in LBD.
  6. Establish a publicly available library of all α-syn and Aβ species characterized by the CWOW.

Achieving the overall aims of the Lewy Body Dementia Center Without Walls will provide significant novel insight into the structural characteristics of alpha-synuclein and amyloid-beta subspecies in LBD, reveal mechanisms contributing to the etiology of LBD, and lead to a better understanding of the determinants of disease progression. New insight into the cross talk between α-syn and Aβ in aggregation and neurotoxicity will expedite future research efforts, identify druggable targets and aid in the development of intervention strategies that may not only prevent onset but also provide clinically relevant, symptomatic benefits to patients with LBD.

Research team

Led by Mayo Clinic neuropathologist Dennis W. Dickson, M.D., and neuroscientist Pamela J. McLean, Ph.D., the Lewy Body Dementia Center Without Walls uses a multidisciplinary approach to bring together 11 investigators with complementary research and technical expertise from six institutions.

Omics research

Genetics, biostatistics and network analyses

Structural biology and biochemistry

Molecular and cellular biology