Cerebral endothelial cell (cEC) and neurovascular stress induced by vascular amyloid β (Aβ) and
tau deposits are early contributors to cerebrovascular damage, blood-brain barrier (BBB)
dysfunction and clearance impairment, precipitating neurodegeneration and neuroinflammation
processes in cerebral amyloid angiopathy (CAA), Alzheimer’s disease (AD) and dementias.
However, the cellular and molecular mechanisms through which Aβ and tau drive cEC and BBB
dysfunction remain to be fully clarified, and possible therapeutic strategies are sorely needed. Our
studies aim to understand the mechanisms of aggregated Aβ and tau toxicity on the cerebral vessels,
in the presence or absence of comorbid cardiovascular risk factors, while testing novel potential
therapeutic strategies against cerebrovascular dysfunction and neurovascular stress in the AD and
CAA brain.
We revealed mitochondrial and metabolic changes mediating the detrimental effects of both
amyloid and tau on cECs, which are directly and causally linked to EC inflammatory activation,
BBB dysfunction, and associated to activation of the pro-apoptotic cascade. We defined how some
of these pathways can be potentiated by cardiovascular risk factors. We also discovered that these
toxic mitochondrial and apoptotic mechanisms are rescued by CA inhibition. Using human cECs
and AD animal models, we tested the potential protective effects of carbonic anhydrase inhibitors or
of the genetic deletion of a mitochondrial CA enzyme on cerebrovascular dysfunction.
These findings improve the understanding of the vascular contributions to AD and dementia, while
unveiling novel molecular targets with high therapeutic potential.
10 Aprile 2026