Synaptic tauopathy in a model of Alzheimer’s disease and traumatic brain injury

Abstract

AbstractBackgroundSynapse loss is an early, pathogenic hallmark of Alzheimer’s disease (AD) and related neurodegenerative conditions. We recently demonstrated that traumatic brain injury (TBI) – the best‐established environmental risk factor for AD – also causes synapse loss, thus establishing a potential pathomechanistic connection between these conditions. One likely contributor is the microtubule associated protein tau. Phosphorylated isoforms of tau can be identified in the brain after TBI and are classically associated with AD‐related pathology. The extent to which these pathoisoforms reach synapses and contribute to their loss, however, is minimally explored.MethodWe combined the PS19 mouse model, which exhibits age‐dependent tau aggregation and synapse loss, with early TBI and subsequent aging to investigate tauopathic synaptic alterations in relation to traumatic and AD‐related processes. TBI was induced with a diffuse, closed‐head injury model called modCHIMERA (Sauerbeck et al, 2018) that causes delayed synapse loss. Synaptic analysis was performed with SEQUIN (Sauerbeck et al, 2020, Reitz et al, 2021), a super‐resolution imaging and analysis platform for quantifying synaptic density as well as nanostructure and molecular features in mammalian neuropil.ResultBoth TBI and expression of the P301S mutation resulted in accumulation of pathoisoforms of tau at synapses and regional synapse loss that evolved over time. Temporal and spatial patterns of tau accumulation varied by phosphoisoform. TBI resulted in an additional burden of synapse loss in PS19 animals, suggesting that TBI may increase the risk of AD through a potentiation of synaptic injury. We are exploring the functional consequences of this connection in ongoing experiments.ConclusionThese studies demonstrate novel subcellular targets of pathological tau isoforms and suggest that tau is a key factor in synapse loss in TBI and AD. This shared mechanism may help explain the elevated risk of AD following TBI. Further characterization of these processes may suggest ways to sever this link, as well as prevent synapse loss in primary AD.