Alzheimer's disease, Cerebral amyloid angiopathy and the blood-brain barrier, molecular targets and novel therapeutic strategies
A common neurobiological thread underlies many neurodegenerative disorders, namely progressive degenerative death of neurons and loss of synaptic connections, ultimately leading to cognitive impairment and in some cases dementia. However, in recent years, dementia, more specifically AD, is being recognized more and more as a multi-factorial disorder or syndrome, with the presence of multiple concurrent pathological events leading to loss of optimal neuronal functioning and the development of cognitive impairment. Among these events, cerebral vascular dysfunction, which also results in the reduction of brain oxygen and glucose supplies, has been recognized as one of the earliest pathological features found in the majority of AD patients. Indeed, cerebral amyloid angiopathy (CAA), the deposition of amyloid at the cerebral vessel walls, is present in 80-90% of AD cases and in many non-AD subjects, increasing with age. Today we also know that mixed pathology dementias account for more than half of the total cases, with amyloidosis and vascular disease being the most frequent combination.
Cerebral endothelial cells (cECs) lining the vessel walls regulate blood brain barrier (BBB) and neurovascular unit function, and their failure causes micro-hemorrhages, neurodegeneration and neuroinflammation processes in Alzheimer’s disease (AD). Our research focuses on understanding the mechanisms by which cECs and neurovascular unit function are altered by AD and cerebral amyloid angiopathy (CAA) pathology, and how cEC dysfunction mediates BBB failure and inflammatory alterations. Particularly, this lecture will focus on the detrimental effects of both pathological amyloid β (Aβ) and tau aggregates in cECs, and how these pathologies affect mitochondrial function, metabolism and cell death mechanisms. Moreover, it will explore how comorbid cardiovascular risk factors such as hypertension, cerebral hypoperfusion and hyperhomocysteinemia act on the same cellular and molecular mechanisms in an additive or synergistic manner with AD pathology, leading to endothelial inflammatory activation and BBB permeability.
As treatment options for dementia are currently limited to conducting damage control on amyloid pathology and managing symptomology, this lecture will also introduce novel potential therapeutic strategies targeting vascular and clearance mechanisms through the rescue of mitochondrial dysfunction.
16 Maggio, 2025