Role of alpha-synuclein-dependent network hyperactivity in Lewy Body Dementia

University Of Minnesota, Minneapolis MN

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Abstract

SUMMARY/ABSTRACT Dementia due to Parkinson?s disease (PD) and Dementia with Lewy Bodies (DLB) is the second most common degenerative dementia in the world. Unfortunately, there are currently no therapies to slow or halt the progression of dementia associated with PD/DLB. Seizures or myoclonus occur in over half of DLB patients, and these symptoms could hasten cognitive decline. Seizures associated with PD and DLB deserve more attention because, despite the harmful impact on the patients, seizure activity can go unrecognized and untreated. Our preliminary studies show that abnormal ?-synuclein (?S) is directly linked to cognitive deficits AND increased epileptic activity is related to cognitive dysfunction in models of ?-synucleinopathy. We also show that ?S dependent synaptic and cognitive deficits require endogenous tau expression. This is reminiscent of data showing that the tau-dependence of cognitive deficits and increase epileptic activity in the J20 mouse model Alzheimer?s disease (AD). Preventing epileptic activity with antiseizure drugs improves memory in models of AD and antiseizure drugs are currently in early phase clinical trials for AD. However, antiseizure drugs have not been investigated thoroughly in models of ?-synucleinopathy. To better define the role of seizure activity in DLB, following aims are proposed: Aim 1. Determine the causal relationship between the epileptiform activity and ?S-dependent cognitive deficits. Aim 2. Determine if postnatal expression of A53T mutant human ?S in forebrain excitatory neurons is sufficient to cause increased epileptiform activities and cognitive deficits. Aim 3. Determine if A? and ?S act synergistically in development of epileptiform activity and cognitive deficits. Aim 4. Determine the extent of subclinical epileptiform activity in people with dementia with Lewy bodies (DLB). The results of this investigation could lead to new strategies, such as reducing tau levels and antiseizure drugs, as therapies for PD and DLB.