New therapeutic targets in the neurovascular pathway in Alzheimer's disease.
Recent findings indicate that neurovascular dysfunction is an integral part of Alzheimer's disease (AD). Changes in the vascular system of the brain may significantly contribute to the onset and progression of dementia and to the development of a chronic neurodegenerative process. In contrast to the neurocentric view, which proposes that changes in chronic neurodegenerative disorders, including AD, can be attributed solely to neuronal disorder and neuronal dysfunction, the neurovascular concept proposes that dysfunction of non-neuronal neighboring cells and disintegration of neurovascular unit function may contribute to the pathogenesis of dementias in the elderly population, and understanding these processes will be crucial for the development of new therapeutic approaches to normalize both vascular and neuronal dysfunction. In this review, I discuss briefly the role of vascular factors and vascular disorder in AD, the link between cerebrovascular disorder and AD, the clearance hypothesis for AD, the role of RAGE (receptor for advanced glycation end products) and LRP (low density lipoprotein receptor related protein 1) in maintaining the levels of amyloid beta-peptide (Abeta) in the brain by controlling its transport across the blood-brain barrier (BBB), and the role of impaired vascular remodeling and cerebral blood flow dysregulation in the disease process. The therapeutic strategies based on new targets in the AD neurovascular pathway, such as RAGE and LRP receptors, and on a few selected genes implicated in AD neurovascular dysfunction (e.g., mesenchyme homeobox gene 2 and myocardin) are also discussed.
Zlokovic
Berislav V
BV
Center for Neurodegenerative and Vascular Brain Disorders, Departments of Neurosurgery, University of Rochester Medical School, Rochester, New York 14642, USA. Berislav_Zlokovic@urmc.rochester.edu
D000544:Alzheimer Disease / Q000209:etiology* / Q000378:metabolism / Q000628:therapy*; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D001812:Blood-Brain Barrier / Q000503:physiopathology; D002560:Cerebrovascular Circulation / Q000502:physiology*; D002561:Cerebrovascular Disorders / Q000150:complications*; D006801:Humans; D026503:Low Density Lipoprotein Receptor-Related Protein-1 / Q000378:metabolism; D008954:Models, Biological; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic / Q000378:metabolism
D016229:Amyloid beta-Peptides; C514519:LDLR-related protein 1A, human; D026503:Low Density Lipoprotein Receptor-Related Protein-1; D000067759:Receptor for Advanced Glycation End Products; D011971:Receptors, Immunologic