Redox-based Targeting of Cerebrovascular Dysfunction in AD

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Summary Increasing evidence suggests the common occurrence of cerebrovascular dysfunction shared between Alzheimer's disease (AD) and vascular conditions/diseases thereby suggesting a mechanistic link characterized by the loss of structural and functional integrity of the neurovascular unit (NVU) in turn contributing to cognitive impairment. In terms of molecular mechanisms of vascular damage, experimental findings emphasize the major role that oxidative stress (OS) plays in inducing cerebrovascular dysfunction, which could be exacerbated by co-morbid conditions such as type-2 diabetes (T2DM). Although OS has long been considered a therapeutic target in neurodegenerative diseases in general, antioxidant therapies so far have mostly failed clinically. This setback notwithstanding, an alternative redox-based therapeutic approach targeting redox homeostasis per se might offer a better option. Here, we consider and test the hypothesis that boosting endogenous anti-oxidant mechanisms particularly within the vulnerable cerebrovasculature might have a vasculoprotective role and hence, improved cognitive outcome in a model of AD with or without co- morbid T2DM. The major endogenous redox system targeted is the Thioredoxin (TRX)-Thioredoxin-interacting protein (Txnip) duo with their mutually antagonistic redox roles. The studies use PDAPP Tg (J20) and Tg-SwDI mice crossed with an inducible mural cell (vascular smooth muscle cell/pericyte) reporter line to enable efficient monitoring of pericyte loss or their altered vascular coverage as well as for Cre-loxP conditional deletion of Txnip in mural cells. The Tg mice will be subjected to a non-genetic T2DM paradigm i.e., a combination of high fat diet (HFD) and low-dose of streptozotocin (STZ). We will employ a redox-based dual strategy i.e., the use of a Trx1 peptidomimetic (Aim 1) and genetic deletion of Txnip in mural cells (Aim 2) to target the Trx redox system in this model and evaluate their vasculoprotective effects in terms of altered structure-function indices of cerebrovascular dysfunction including altered BBB permeability and vasoreactivity correlated with cognitive outcome. The findings of this exploratory study are expected to support a redox-based vasculoprotective approach (including potential use of brain non-penetrant drugs) to treat AD and the related complex etiology of `vascular contributions to cognitive impairment and dementia (VCID)'.