GRK2 Overexpression is a primary hallmark of vascular hypoperfusion and mitochondrial lesions during early Alzheimer disease: New target for drug treatment?

Increasing evidence points to vascular damage as an early contributor to the development of two leading causes of age-associated dementia, namely Alzheimer disease (AD) and AD-like pathology such as stroke. This review focuses on the role of G protein-coupled receptor kinases, particularly GRK2 as they relate to dementia and how the cardiovasculature is involved in cerebrovascular pathogenesis. Any possible involvement of GRKs in AD pathogenesis is an interesting notion, whose exploration may help bridge the gap in our understanding of the heart-brain connection in relation to neurovisceral damage and vascular complications in AD. The a priori basis for this inquiry stems from the fact that kinases of this family regulate numerous receptor functions in the brain, the myocardium and elsewhere. The aim of this review is to discuss the finding of GRK2 overexpression in the context of the early AD pathogenesis, since increased levels of GRK2 immunoreactivity were found in vulnerable neurons from AD patients and from a two-vessel occlusion (2-VO) mammalian model of cerebral ischemia. Also, we consider the consequences for this overexpression as a loss of G-protein coupled receptor (GPCR) regulation, as well as suggest a potential role for GPCRs and GRKs in a unifying theory of AD pathogenesis and cerebrovascular disease. We therefore synthesize this newer information in an attempt to put it into context with GRKs as regulators of diverse physiological cellular functions. The complex mechanisms, which underlie regulation of GRK expression, degradation and function now are being elucidated and the levels of these kinases have been described to be altered in several pathological situations, such as cardiac failure, hypertension, inflammation and cancer. We suggest that GRKs may contribute to the development of pathology, making these proteins potential diagnostic and therapeutic targets for future pharmacological intervention.