Despite decades of neuropathological investigations of Parkinson's disease, few strategies have addressed fundamental degenerative processes beyond the classic pathological hallmarks of neuronal degeneration and protein aggregates. Our previous work has shown that lipid levels are elevated in the brain in Parkinson's disease including in areas of the brain also affected in dementia, and that there is a shift in the distribution of lipids within neurons and glial cells in Parkinson's disease. Appropriate movement of lipids between neurons and glial cells in the brain (through lipid transporters called apolipoproteins) is essential for maintaining metabolic integrity and health of neurons. Recent genetic, biological and immunological studies, including our preliminary data, reveal that apolipoproteins (apolipoprotein E, APOE) and lysosomal enzymes (glucocerebrosidase, GBA1) are likely heavily involved in neuronal and glial degenerative processes leading to Parkinson's disease and dementia. While the genetic risks for Parkinson's disease by APOE and GBA1 are well documented, their biological and brain cell interactions causing disease are not clearly understood. As a consequence, no treatments exist based on any insight about APOE and lipid load for Parkinson's disease dementias.

The majority of patients with Parkinson's disease will progress to cognitive dysfunction and dementia, and there is no treatment. Resolving the critical questions about interactions between neurons and glia in lipid transfer and inflammatory cascades are urgently needed to develop treatments for patients with Parkinson's disease who are at risk for developing cognitive dysfunction.

The proposed experiments will utilize advanced human neuron and glial phenotypic in vitro assays (Specific Aim 1), and a unique in vivo platform where individual glial function can be studied (Specific Aim 2), to address the central question: How does APOE adapt to GBA1-induced glycolipid load in neurons and glia, to modify cognitive disturbances and modulate neural dysfunction and pathophysiology?

This work will discover fundamental underlying mechanistic networks controlling neuronal and glia lipid transfer and storage in Parkinson's disease dementias. At completion of this 4-year project, the results generated will provide essential knowledge and new insights in understanding the critical neuronal and glial failures that lead to lipid disturbances in Parkinson's disease dementia. The proposed work will identify methods, biological targets and specific cellular markers to be able to discover and treat cognitive dysfunction in Parkinson's disease.

This experimental work is of critical importance. Only with accurate biological information and insight can reasonable preclinical discovery work precede that will significantly accelerate meaningful clinical trials in patients, to be conducted with a higher chance of success. The proposed cellular road map is significant for pharmacological and biological interventions against the dysfunction and degeneration that underlies cognitive dysfunction in Parkinson's disease. In summary, the designed experiments here provide the necessary framework to discover and propose new biomarkers that in all cases must come from cellular signals, to be evaluated in Parkinson's disease dementia in the clinical scenario, and conversely interventions that reduce the expression of these biomarkers as evidence of successful treatment of causative factors. Agents or therapies that restore lipid transport and homeostasis among neurons, astrocytes, and microglia could potentially correct pathogenesis and disease progression in Parkinson's disease leading to cognitive dysfunction.