Investigating the mechanisms underlying synaptic and cognitive deficits in alpha-synucleinopathies

Abstract

Parkinson’s disease dementia (PDD) and dementia with Lewy bodies (DLB) are clinically and neuropathologically related -synucleinopathies that collectively constitute the second leading cause of neurodegenerative dementias. While alpha-synuclein (aS) abnormalities are directly implicated in PDD and DLB pathogenesis, it is unknown how aS contributes to memory loss. Previously, we found that familial Parkinson’s disease (PD)-linked human mutant A53T aS causes aberrant mislocalization of tau to dendritic spines in neurons, leading to postsynaptic deficits. Thus, we directly tested if the progressive postsynaptic and memory deficits observed in a mouse model of alpha-synucleinopathy (TgA53T) are mediated by tau. Significantly, removal of endogenous mouse tau expression in TgA53T mice (TgA53T/mTau-/-) completely ameliorates cognitive dysfunction and concurrent synaptic deficits. Memory deficits in TgA53T mice were also associated with hippocampal circuit remodeling linked to chronic network hyperexcitability. This remodeling was absent in TgA53T/mTau-/- mice, indicating that postsynaptic deficits, aberrant network hyperactivity, and memory deficits are mechanistically linked. Our results implicate tau as a mediator of human mutant A53T aS-mediated abnormalities and suggest a mechanism for memory impairment that occurs via synaptic dysfunction rather than synaptic or neuronal loss. Fibrillar species of aS have also recently been implicated as a pathogenic component of synucleinopathies, capable of transmission between neurons and brain regions including the hippocampus. However, how aS fibrils impact hippocampal function and contribute to memory deficits are not well understood. We hypothesized that aS fibril-induced synaptic changes could be mediated through interactions with other proteins, including tau. Primary hippocampal neurons acutely exposed to fibrillar aS species display tau missorting to dendritic spines and both pre and postsynaptic electrophysiological deficits. However, some of these findings may be a product of concentration-dependent fibril-induced spine collapse. Importantly, the pathways behind fibril-mediated tau missorting and synapse loss could be differentiated in vitro. Taken together, these studies suggest that pathological aS fibrils and aggregates may act through distinct intracellular and extracellular mechanisms to contribute to neuronal dysfunction and neuronal toxicity. These approaches and results collectively indicate that pathological mutant and aggregated species of aS can drive synaptic deficits and represent potential therapeutic targets for amelioration of memory deficits in alpha-synucleinopathies.