Alzheimer’s disease (AD) is the leading cause of dementia worldwide. It compromises patients’ daily activities owing to progressive cognitive deterioration, which has elevated direct and indirect costs. Although AD has several risk factors, aging is considered the most important. Unfortunately, clinical diagnosis is usually performed at an advanced disease stage when dementia is established, making implementation of successful therapeutic interventions difficult. Current biomarkers tend to be expensive, insufficient, or invasive, raising the need for novel, improved tools aimed at early disease detection. AD is characterized by brain atrophy due to neuronal and synaptic loss, extracellular amyloid plaques composed of amyloid-beta peptide (Aβ), and neurofibrillary tangles of hyperphosphorylated tau protein. The visual system and central nervous system share many functional components. Thus, it is plausible that damage induced by Aβ, tau, and neuroinflammation may be observed in visua...

A large number of Alzheimer patients demonstrate cerebrovascular pathology, which has been assumed to be related to β-amyloid (Aβ) deposition. Aβ peptides have been described to inhibit angiogenesis both in vitro and in vivo, and deregulation of angiogenic factors may contribute to various neurological disorders including neurodegeneration. One of the key angiogenic factor is the vascular endothelial growth factor (VEGF). Increased levels of VEGF have been observed in brains of Alzheimer patients, while the functional significance of VEGF up-regulation in the pathogenesis and progression of AD is still a matter of debate. To test whether VEGF may affect neuronal APP processing, primary neuronal cells derived from brain tissue of E16 embryos of Tg2576 mice were exposed with 1 ng/ml VEGF for 6, 12, and 24h, followed by monitoring formation and secretion of soluble Aβ peptides, release of the human APP cleavage products, sAPPβswe and sAPPα, into the culture medium as well as the activities of α- and β-secretases in neuronal cell extracts. Exposure of primary neuronal cells by VEGF for 24h led to slightly reduced sAPPβ release, accompanied by decreased β-secretase activity 12h after VEGF exposure. Incubation of neurons by the VEGF receptor antagonist and angiogenesis inhibitor SU-5416 for 24h resulted in increased release of sAPPβswe, and strikingly enhanced secretion of Aβ peptides into the culture medium, which was accompanied by a significant increase in β-secretase activity, as compared to control incubations. The SU-5416-induced effects on APP processing could not be suppressed by the additional presence of VEGF, suggesting that SU-5416 affects pathways that are apparently independent of VEGF receptor signaling. The data obtained indicate that VEGF-driven mechanisms may affect APP processing, suggesting a link of angiogenesis and pathogenesis of Alzheimer's disease.

There is a perfusion deficit in Alzheimer's disease (AD), commencing in the precuneus and spreading to other parts of the cerebral cortex. The deficit anticipates the development of dementia, contributes to brain damage, and is caused by both functional and structural abnormalities of the cerebral vasculature. Most of the abnormalities are probably secondary to the accumulation of Aβ but the consequent hypoperfusion may, in turn, increase Aβ production. In the early stages of disease, abnormalities that cause vasoconstriction predominate. These include cholinergic vascular denervation, inhibition of endothelial nitric oxide synthase, increased production of endothelin-1 production and possibly also of angiotensin II. Patients with AD also have an increased prevalence of structural disease of cerebral microvessels, particularly CAA and capillary damage, and particularly in the later stages of disease these are likely to make an important contribution to the cerebral hypoperfusion...