Integrative analysis of proteomics and transcriptomics to delineate vesicular transport related protein abnormalities related to Alzheimer's, Lewy body and mixed Pathologies

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PROJECT SUMMARY/ABSTRACT Dementia has a significant disease burden worldwide with around 50 million people having it. Alzheimer’s disease (AD), the most common etiology of dementia is characterized by abnormal accumulation of amyloid beta(Aβ) and tau proteins in the brain. After AD, dementia with Lewy bodies (DLB) is often noted among the top two common forms of dementia and includes α-synuclein protein (α-syn) neuronal inclusions as a key pathology marker. Even as AD and DLB are common, neuropathology studies have consistently noted that rather than a single underlying etiology, there is a high frequency of patients where more than one pathology (mixed pathology) contributes to the dementia syndrome. The pathophysiological impact of these pathologies when together, on the initiation and progression of neurodegeneration and development of cognitive decline is yet to be comprehensively understood. The research at the foundation of this R21 is a clinical translational study that uses systems biology and proteomics techniques to characterize the properties of differentially expressed genes and proteins between patients with AD or DLB pathology alone and among those patients with mixed dementia pathology of AD and DLB pathology. In this work we will clarify if there is a mechanistic reason some brains are more prone to develop mixed pathology of ADP-LRP (Aβ-α-syn) over others that have predominantly Aβ or α-syn. Prior studies in AD and DLB suggest dysregulation of endosomal-lysosomal pathways. As clinical AD dementia in these prior studies often included mixed pathology, it has been challenging to disentangle the role for endosomal-lysosomal dysregulation for each individual pathology. Our preliminary data leads us hypothesize that presence of Aβ pathology in the brain along with co-existing cellular vesicular transport abnormalities makes it more likely for the development of mixed pathologies including ADP-LRP. We will evaluate this hypothesis by proteomic and transcriptomic evaluation of brain, CSF and plasma of three patient groups (AD, DLB and mixed AD-DLB) and among age and sex matched normal controls. We will confirm and validate our data against data from other large national data (ADNI, Accelerating Medicines Partnership-AD). We will develop a model paradigm to assess the role for dysregulation of vesicular transport proteins in mixed pathologies at the genetic, transcriptional and proteomic levels. If the hypothesis and models are validated, scientific insights from this research will help identify the nature of synergistic relationship between these pathologies to develop better therapeutic targeting of mixed pathology dementia. If the hypothesis is found to be not true, the findings from this study will still represent a significant advance in our knowledge of variability in individual proteomic and transcriptomic signatures in the face of neurodegenerative disease pathology. The results of this will be useful both clinically and in designing and interpreting future research outcomes.