Platelets and Cerebral Amyloid Angiopathy

Alzheimer`s disease is a chronic neurodegenerative disorder characterized by the presence of beta-amyloid depositions in brain (plaques) and vessels (cerebral amyloid angiopathy), tau pathology, cerebrovascular damage, inflammation and cell death of neurons. The reasons for development of Alzheimer`s disease are not clear, but vascular risk factors may play a role (Humpel, 2010). These vascular risk factors are e.g. cholesterol, hypertension or hyperglycemia. Recently we were able to show in a FWF-supported project (P19122-B05) that hypercholesterolemia in rats leads to cognitive impairment, degeneration of cholinergic neurons, inflammation and small (anti-rat IgG+) bleeds in the cortex (Ullrich et al., 2010). We hypothesize that small cortical bleeds may play a role in the development of vascular dementia and/or Alzheimer`s disease, and that blood-derived toxic molecules as well as blood cells may enter the brain and may provide a basis for development of cerebral amyloid angiopathy. The first aim of this project is to further characterize these small cortical bleeds in an Alzheimer mouse model (triple transgenic) and hypercholesterolemia and hyperglycemic mouse models and to determine a time- and brain region specific pattern. With more sophisticated methods (MRI scans, co-localization and confocal microscopy, electron microscopy and microdissection and multiplex ELISAs) we aim to further determine if the small bleeds occur alone or together with beta-amyloid depositions. In the last part of this project we want to explore if blood cells (erythrocytes, monocytes and platelets) enter the brain. Especially we aim to focus on platelets (which contain high amounts of amyloid-precursor protein which is cleaved into beta-amyloid) and we will study if a dysregulated beta-amyloid from platetels may contribute to cerebral amyloid angiopathy. We suggest that chronic mild vascular risk factors over decades may induce a large number of small bleeds in the brain and that platelets migrate to these sites, and process and release beta-amyloid which is deposited in vessels. This project may show that vascular risk factors play a role in the development of Alzheimer`s disease and may introduce therapeutic strategies to repair and counteract bleeds and/or to block dysregulated platelets in the brain.

Alzheimers disease is a severe neurodegenerative disorder of the brain and characterized by extracellular (beta-amyloid) and intraneuronal (tau) depositions, as well as dramatic damage on brain vessels, including depositions of beta-amyloid in vessels (the so called cerebral amyloid angiopathie). In order to repair these damaged vessels, blood platelets (thrombocytes) become activated, they migrate to the lesion site and repair the "holes" in the vessels by clotting. It is interesting to note, that platelets can process and secrete beta- amyloid also in blood, and it may play a role in clotting. Our working hypothesis is that platelets become pre-activated in humans over decades, and may produce and secrete pathological beta-amyloid, which may play a role in the progession of Alzheimers disease. In our present FWF project P24734 we show in an Alzheimer mouse model, that platelets become pre-activated already in an early stage. These pre-activated platelets may also damage healthy vessels and induce inflammatory processes and cause depositions of beta- amyloid. Further, the analysis of platelets and their proteins may allow to help to diagnose Alzheimers disease. Our work suggests that platelets may become therapeutic targets in an early phase of Alzheimers disease. Future work will show, if and when platelets become pre-activated in humans, and if it is possible to modulate the activity of platelets during Alzheimer progression without any risky side effects on blood clotting.