While amyloid plaques and tau tangles are the classic hallmarks of Alzheimer’s disease (AD), synapse loss represents an equally critical but often overlooked feature that contributes directly to cognitive decline. Synapses enable communication between neurons and are fundamental to learning, memory, and behavior. They fall into two main categories that work together to produce an incredible range of nuanced and coordinated firing patterns: excitatory, which increase the likelihood that signals will be passed along, and inhibitory, which increase the likelihood that signals will be blocked. Excitatory synapses, particularly glutamatergic synapses that release the neurotransmitter glutamate, are especially vulnerable in AD. Their degeneration begins early in disease progression, long before widespread neuronal death, and continues throughout the disease course, and synapse loss correlates closely with cognitive decline.
Despite their importance, the molecular mechanisms driving synapse loss in AD are not fully understood. Accumulating evidence indicates that pathological forms of amyloid beta and tau disrupt key signaling pathways essential for synapse formation and maintenance. Among these disrupted pathways, the planar cell polarity (PCP) pathway, which normally regulates synaptic organization and stability, has emerged as a promising candidate for further investigation. The PCP pathway’s role in maintaining synaptic architecture makes its disruption particularly relevant to the early synaptic vulnerability observed in AD. Understanding how amyloid beta and tau interfere with PCP signaling may reveal why synapses are selectively lost in AD and identify potential therapeutic targets for synaptic protection.
Dr. Zou and Dr. Jiang focus their research on how a specific group of proteins in the PCP pathway controls the connections between neurons in brain areas critical for memory and thinking. This complex of proteins includes three that span the cell membrane (Frizzled, Celsr, and Vangl) and three found inside the cell (Disheveled/Dvl, Prickle, and Diego). Previous work from the Zou Lab showed that these proteins perform opposing functions: stabilizing proteins like Celsr3, Frizzled3, and Prickle1/2 maintain synaptic connections by forming a trans-synaptic protein complex mediated by homophilic interaction between the Cadherin domains of Celsr3 proteins on the presynaptic and postsynaptic membranes, while Vangl2 promotes breakdown of this trans-synaptic complex and thus the synapses. A cell surface receptor, Ryk, which interacts with Frizzled and Vangl2, also destabilizes synapses. Dr. Zou’s group showed that amyloid oligomers can bind to the extracellular region of Celsr3 required for interaction with Frizzled3, disrupting this delicate balance and allowing Vangl2-Ryk complexes to drive pathological synapse loss. The Zou Lab also obtained evidence that the PCP pathway is impacted in tau (PS19) mouse models, as well as in human brain tissue from individuals with AD. In this collaborative proposal, Zou teams up with Jiang, whose lab studies mechanisms of tauopathy and has developed an elegant approach to study oligomeric tau, to explore whether and how toxic tau oligomers disrupt the PCP pathway in glutamatergic synapses.
Drs. Zou and Jiang hypothesize that toxic tau species impair synaptic stability by tipping the balance of PCP signaling toward synapse disassembly. They will investigate this hypothesis through three experimental aims. In aim one, they will test whether tau oligomers and fibrils from human post-mortem brain and PS19 tau mouse model disrupt the PCP pathway by binding to its proteins. Their studies will utilize neurons and brain tissue from both human patients and controls, as well as from tau and amyloid mouse models, to determine the translatability of their findings. In aim two, they will test whether tau oligomers cause synapse degeneration by reducing the stability of the PCP protein complex that typically maintains synaptic connections. In mouse hippocampal and primary neuronal cultures, they will map the timeline of synapse degeneration and identify which PCP proteins are affected first, shedding light on how the loss of these proteins contributes to the breakdown of synaptic structure. In aim three, they will determine whether blocking synapse-destabilizing proteins can prevent tau-mediated synaptic degeneration. They will analyze synapse number, size, and memory-related function in two new mouse models: one lacking Vangl2 and another lacking Ryk. Overall, this work could reveal a new mechanism underlying tau’s contributions to synapse loss while identifying specific intervention points that could help protect brain function in the face of disease.
