Tau-dependent cognitive deficits in alpha-synucleinopathies

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Summary/Abstract: Parkinson’s disease (PD) is the second most common late-onset neurodegenerative disease with the largest relative increase in mortality rates among all neurological disorders. PD is traditionally considered a motor disorder, characterized by the loss of dopaminergic neurons of the SNpc, and the presence of fibrillar cytoplasmic inclusions called Lewy bodies and Lewy neurites. However, a more global perspective on the PD is developing, motivated by pathological and clinical findings that extend beyond the basal ganglia. In particular, the majority of PD patients meet criteria for a secondary diagnosis of mild cognitive impairment that progresses dementia, a significant contributor to disease morbidity and mortality. The emerging view is that the abnormalities in α-synuclein (αS) may be responsible for motor and non-motor symptoms in PD and Dementia with Lewy Bodies (DLB). Significantly, we recently found that abnormal αS can cause post-synaptic deficits in vitro and in vivo via a microtubule associated protein tau (MAPT) dependent mechanism. In this proposal, we will directly determine the following hypothesis: 1) Pathogenic αS species produce cognitive decline tau-dependent post-synaptic mechanisms and 2) MAPT-dependent postsynaptic deficits caused by exogenous αS fibrils/oligomers contribute to cognitive deficits in sporadic PD and DLB. To determine the mechanistic basis for cognitive deficits in α-synucleinopathy, we propose following aims: 1) Determine whether tau is required for αS dependent synaptic and cognitive deficits; 2) Determine if mutant αS-dependent AMPAR deficits and memory deficits are caused by multiple pathways; 3) Determine whether hippocampal αS pathology and somatodendritic tau mislocalization correlates with dementia in PD; 4) Determine if exogenous pathogenic αS induces pre- and/or post-synaptic deficits; and 5) Determine if pathogenic αS induces defects in synaptic plasticity and memory in a tau dependent manner.