Fyn kinase inhibition reduces protein aggregation, increases synapse density and improves memory in transgenic and traumatic Tauopathy.

Accumulation of misfolded phosphorylated Tau (Tauopathy) can be triggered by mutations or by trauma, and is associated with synapse loss, gliosis, neurodegeneration and memory deficits. Fyn kinase physically associates with Tau and regulates subcellular distribution. Here, we assessed whether pharmacological Fyn inhibition alters Tauopathy. In P301S transgenic mice, chronic Fyn inhibition prevented deficits in spatial memory and passive avoidance learning. The behavioral improvement was coupled with reduced accumulation of phospho-Tau in the hippocampus, with reductions in glial activation and with recovery of presynaptic markers. We extended this analysis to a trauma model in which very mild repetitive closed head injury was paired with chronic variable stress over 2 weeks to produce persistent memory deficits and Tau accumulation. In this model, Fyn inhibition beginning 24 h after the trauma ended rescued memory performance and reduced phospho-Tau accumulation. Thus, inhibition of Fyn kinase may have therapeutic benefit in clinical Tauopathies.

Alzheimer's Disease Risk Factor Pyk2 Mediates Amyloid-ß-Induced Synaptic Dysfunction and Loss.

Dozens of genes have been implicated in late onset Alzheimer's disease (AD) risk, but none has a defined mechanism of action in neurons. Here, we show that the risk factor Pyk2 (PTK2B) localizes specifically to neurons in adult brain. Absence of Pyk2 has no major effect on synapse formation or the basal parameters of synaptic transmission in the hippocampal Schaffer collateral pathway. However, the induction of synaptic LTD is suppressed in Pyk2-null slices. In contrast, deletion of Pyk2 expression does not alter LTP under control conditions. Of relevance for AD pathophysiology, Pyk2-/- slices are protected from amyloid-ß-oligomer (Aßo)-induced suppression of LTP in hippocampal slices. Acutely, a Pyk2 kinase inhibitor also prevents Aßo-induced suppression of LTP in WT slices. Female and male transgenic AD model mice expressing APPswe/PSEN1ΔE9 require Pyk2 for age-dependent loss of synaptic markers and for impairment of learning and memory. However, absence of Pyk2 does not alter Aß accumulation or gliosis. Therefore, the Pyk2 risk gene is directly implicated in a neuronal Aßo signaling pathway impairing synaptic anatomy and function.SIGNIFICANCE STATEMENT Genetic variation at the Pyk2 (PTK2B) locus is a risk for late onset Alzheimer's disease (AD), but the pathophysiological role of Pyk2 is not clear. Here, we studied Pyk2 neuronal function in mice lacking expression with and without transgenes generating amyloid-ß (Aß) plaque pathology. Pyk2 is not required for basal synaptic transmission or LTP, but participates in LTD. Hippocampal slices lacking Pyk2 are protected from AD-related Aß oligomer suppression of synaptic plasticity. In transgenic AD model mice, deletion of Pyk2 rescues synaptic loss and learning/memory deficits. Therefore, Pyk2 plays a central role in AD-related synaptic dysfunction mediating Aß-triggered dysfunction.