Gene therapy targeting synaptopathy linked with Alzheimer's and Parkinson's disease

Synaptic Plasticity pertains to the synapse's tendency to adapt fresh information and is a crucial step in the establishment of brain circuits that aid in memory formation. It has become one of the most intensively researched topics in all of neuroscience. Pieces of evidence are accumulating that synaptopathy (altered synaptic plasticity) mechanisms contribute to Alzheimer's disease (AD) and Parkinson's disease (PD). Toxins responsible for synaptopathy and aberrant neurotransmitter (NT) release at synapses are the aggregates of amyloid-β (Aβ) (amyloidopathy) and hyperphosphorylated tau (tauopathy). Amyloidopathy and tauopathy contributes to synaptopathy in AD. Defective NT release at the synaptic interface generates various negative consequences related with changed activity of synaptic gene, proteins, and Ca²⁺ homeostasis necessary for synaptic plasticity. Great attention has been paid to α-synuclein (ASN)-dependent synaptopathy and the fundamental processes behind excessive dopaminergic nerve injury in PD. The familial-PD is caused by mutations in SNCA, LRRK2, Parkin, PINK1, and DJ-1 genes. APP, PSEN1, and PSEN2 gene variants are associated with familial AD. The genetic scissor techniques such as CRISPR and AAV delivery are based on the unique capacity to modify DNA at the base-pair level, which makes them a promising tool for the more advanced and tailored treatments for AD and PD. The purpose of this review was to examine gene therapies targeting synaptopathy, amyloidopathy and tauopathy which are presently undergoing clinical and pre-clinical trials with the aim of increasing synaptic function in AD and PD.