Preclinical investigation of common mechanistic links between aberrant protein aggregation and blood-brain barrier dysfunction in Alzheimer's disease and Alzheimer's related dementias (AD/ADRD)

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PROJECT SUMMARY The blood-brain barrier (BBB) has a fundamental role in maintaining brain tissue homeostasis. While dysfunction of the BBB is a common feature of many neurodegenerative diseases, including Alzheimer’s disease (AD) and AD-related dementias (ADRD), but also small vessel diseases (SVD) such as cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL), it is still unclear whether BBB dysfunction precedes the onset of neurological disorders or is a consequence of their aggravating pathology. Converging evidence indicates that dysfunction of the BBB correlates with an abnormal perivascular deposition and aggregation of proteins such as amyloid-β (Aβ) and tau in AD, or granular osmiophilic material (GOM) and the NOTCH3 ectodomain in CADASIL. These proteins are known to interact with the proteins that make up the extracellular matrix (ECM) and the basement membranes of cerebral blood vessels. Cumulative protein aggregation leads to functional impairment of the ECM and causes damage to the cellular components of the neurovascular unit (NVU), promoting BBB breakdown and affecting the mechanisms of protein transport across the BBB. Thus, there is a vicious cycle between BBB dysfunction and aberrant protein accumulation that progresses with age, leading to cognitive impairment and death. Understanding this cycle is crucial to elucidate the mechanistic links between BBB dysfunction and dementia, and to identify therapeutic opportunities to preserve BBB function. We hypothesize that aberrant protein accumulation and BBB dysfunction contribute synergistically in AD/ADRD and CADASIL through a common mechanistic link. Using well-established mouse models of AD and CADASIL, we propose to investigate the effects of perivascular protein aggregation on both structural (Aim 1) and functional (Aim 2) properties of the BBB, to understand how perivascular protein aggregation relates to structural changes of the NVU that leads to BBB dysfunction. We will then investigate whether the mechanical disruption of the BBB contributes to perivascular protein deposition and aggregation (Aim 3). These experiments will provide crucial knowledge on the molecular and cellular mechanisms of interaction between protein aggregation and BBB breakdown, and may ultimately unravel novel therapeutic targets aimed at preserving cerebrovascular health and BBB function.