Alzheimerʹs disease and angiogenesis

Despite enormous investigative efforts, the pathological basis for Alzheimerʹs disease remains unclear. Suggested mechanisms for the disorder include cerebral hypoperfusion, inflammation, gene polymorphisms, and molecular lesions in the brain. In this Hypothesis, we argue that the vascular endothelial cell has a central role in the progressive destruction of cortical neurons in Alzheimerʹs disease. In Alzheimerʹs disease, the brain endothelium secretes the precursor substrate for the β-amyloid plaque and a neurotoxic peptide that selectively kills cortical neurons. Large populations of endothelial cells are activated by angiogenesis due to brain hypoxia and inflammation. Results of epidemiological studies have shown that long-term use of non-steroidal anti-inflammatory drugs, statins, histamine H2-receptor blockers, or calcium-channel blockers seems to prevent Alzheimerʹs disease. We think this benefit is largely due to these drugsʹ ability to inhibit angiogenesis. If Alzheimerʹs disease is an angiogenesis-dependent disorder, then development of antiangiogenic drugs targeting the abnormal brain endothelial cell might be able to prevent and treat this disease. We suggest several laboratory and clinical approaches for testing our hypothesis.