Vasculoprotection as a Convergent, Multi-Targeted Mechanism of Anti-AD Therapeutics and Interventions

Abstract

Using a variety of animal models of Alzheimer's disease (AD), there have been a number of recent studies reporting varying degrees of success with anti-AD therapeutics. The efficacies are often discussed in terms of the modulatory effects of the compounds tested on identified or assumed targets among the known (or proposed) pathogenic and neuroprotective mechanisms, largely within the context of the dominant amyloid cascade hypothesis. However, it is clear that several of the relatively more efficacious treatments tend to be multifunctional and target multiple pathological processes associated with AD including most commonly, oxidative and metabolic stress and neuroinflammation. Increasing evidence suggests that vascular and neurodegenerative pathologies often co-exist and that neurovascular dysfunction plays a critical role in the development or progression of AD. In this review, we will discuss the significance of vasculoprotection or neurovascular unit integrity as a common, multi-targeted mechanism underlying the reported efficacy of a majority of anti-AD therapeutics--amyloid-targeted or otherwise--while providing a strong support for future neurovascular-based treatment strategies and interventions.

Keywords: Anti-AD therapeutics; blood-brain barrier; cerebrovascular dysfunction; neurovascular unit; type 2-diabetes; vascular risk factors.

Fig 1

Proposed mechanisms and mediators of cerebrovascular dysfunction including neurovascular uncoupling in AD. Cerebrovascular dysfunction in AD is associated with compromised NVU integrity characterized by structural and functional abnormalities (a). Such changes include endothelial and smooth muscle cell damage, pericyte fall out, loss of astrocyte polarization, BBB breakdown, loss of vascular dilatory function and altered blood flow. While blood-borne toxins extravasating through broken BBB can be neurotoxic either directly or through inflammation (not shown), compromised function of uncoupled NVU can lead to neuronal and synaptic degeneration due to hypoperfusion and reduced energy supply (b). A state of hypoxia can result in increased amyloid processing thereby exacerbating amyloid pathology (c) and contributing to a vicious cycle at the cerebrovasculature of vascular damage and CAA formation (d). The oligomeric Aβ can elicit a direct neuro/synaptotoxicity (e). BBB dysfunction may have dual pathological consequences i.e., loss of amyloid transport out of the brain (f) and compromised transport into the CNS of nutrient and trophic factors. The loss of vascular integrity can also impede peri/paravascular drainage of excess amyloid (g). The scheme also depicts an interaction between AD and metabolic/vascular factors at the level of cerebrovasculature (h). A list of anti-AD treatments and interventions discussed in the review in the context of their vasculoprotective roles is shown on the right (i).