Send Orders for Reprints to reprints@benthamscience.net 18 Current Alzheimer Research, 2014, 11, 18-26 Molecular Links Between Endothelial Dysfunction and Neurodegeneration in Alzheimer's Disease Epameinondas Lyros 1,* , Constantinos Bakogiannis 2,# , Yang Liu 1 and Klaus Fassbender 1  Department of Neurology, University of the Saarland, Homburg/Saar, Germany; 2 Department of Cardiology, Univer- sity of the Saarland, Homburg/Saar, Germany Abstract: Alzheimer’s disease (AD) is characterized by a progressive decline of cognitive functions and represents the most common form of dementia and a major cause of morbidity and mortality in the modern, westernized societies. There is accumulating evidence to support the hypothesis that a primary cerebral vascular dysfunction initiates a cascade of events that lead to neuronal injury in Alzheimer’s dementia. The endothelium, in specific, constitutes a part of the blood brain barrier, the dysfunction of which is thought to play an important role to disturbed amyloid- homeostasis and infil- tration of the brain parenchyma with circulating toxic molecules in the disease. Furthermore, the endothelium itself is un- der certain conditions capable of producing neurotoxic and inflammatory factors, whereas common growth factors regu- late the development and maintenance of both neurons and blood vessels. Reliance of both endothelial and neuronal cells on mitochondrial integrity and common molecular pathways for apoptosis also imply that there is a link between vascular pathology and neurodegeneration. The present article intends to review available evidence on molecular players impli- cated in the above mechanisms with the potential to develop biomarkers or novel therapeutic targets. Keywords: Alzheimer's disease, dementia, endothelium, vascular, -amyloid. INTRODUCTION Alzheimer disease (AD) is a progressive neurodegenera- tive disorder causing deterioration of memory and other cog- nitive functions representing the most common cause of de- mentia among the elderly. The main neuropathological hall- marks associated with the disease are extracellular neuritic plaques containing -amyloid peptide (A) derived from - amyloid precursor protein (-APP) and intracellular neurofi- brillary tangles (containing hyperphosphorylated tau protein) [1]. Although vascular comorbidity may be present in up to almost 60% of AD patients [2], widely used clinical criteria traditionally separate between vascular dementia and demen- tia of AD-type. Because of its initial categorization as a non- vascular dementia, the role of vascular factors in the devel- opment of neuronal injury in AD has long been underesti- mated. Accumulating evidence in the literature, however, suggests that there is a complex interplay of vascular and neuronal factors in producing AD pathology. Beyond the obvious connection between stroke and dementia, there are various studies linking cardiovascular risk factors and heart diseases with the onset of Alzheimer’s disease (AD). Post- mortem histologic findings in patients suffering from AD or dementia demonstrated noticeably more atherosclerotic le- sions in the brain vascular system of these patients [3]. Fur- thermore, it has been shown that increased brain deposition of A is associated with increased prevalence of heart *Address correspondence to this author at the Department of Neurology, University of the Saarland, Kirrberger Str. 1, 66421 Homburg/Saar, Germany; Tel: 00496841/16-24103; Fax: 00496841/16-24137; E-mail: lyrosep@upatras.gr # Authors equally contributed diseases. Numerous studies have also demonstrated that the classical cardiovascular risk factors are also closely associ- ated with an increased risk for AD [4]. Hyperhomocysteine- mia, diabetes, hypertension and obesity are among the risk factors associated with increased risk for AD [5-7]. It has also been demonstrated that people suffering from severe atherosclerosis are in higher risk for developing vascular dementia or AD [7, 8]. THE VASCULAR HYPOTHESIS OF AD Excessive accumulation of A in the brain extracellular space is a central event in AD. This may result from over- production, i.e. increased endoproteolytic cleavage of -APP by - and -secretase in the amyloidogenic pathway, im- paired clearance, or both. Rare mutations in either APP or the presenilin (representing -secretase) genes increase pro- duction of the 42 amino acid A form (A42) and cause fa- milial AD with nearly 100% penetrance, suggesting a critical role for A42 also in the etiology of the much more frequent sporadic AD. Elevated A levels lead to formation of oli- gomers and fibrils that  act neurotoxi- cally in vitro and in vivo [1]. It is believed that AD is mainly caused by dysfunction of the nerve axons and synapses shown to depend on soluble A levels and to occur well be- fore deposition of amyloid plaques. According to the classi- cal amyloid hypothesis of Alzheimer’s disease, accumulation of A in the brain is the primary influence driving AD pathogenesis. An alternative hypothesis, the so called two-hit vascular hypothesis of AD, has emerged which states that pathological accumulation of A in the brain is secondary (hit2) to a primary vascular damage (hit1) [9]. According to this hypothesis, an initial disturbance in the microcirculation 1875-5828/14 $58.00+.00 © 2014 Bentham Science Publishers