Cycle 4 project 6

Targeting the brain microvasculature: solving the puzzle of Alzheimer disease?

 

Ananya ChakrabortyPhD student: Ananya Chakraborty, India
Home Institute: Amsterdam Neuroscience; Principle Investigator: Elga de Vries / Wiesje van der Flier
Host Institute: Neuroscience Center Zürich; Principle Investigator: Nitsch, Roger
2nd Host Institute: Bordeaux Neurocampus; Principle Investigator: Klaus, Petry

Executive Summary

Neuropathological hallmarks of Alzheimer disease (AD) are senile plaques containing amyloid-beta and neurofibrillary tangles, consisting of hyperphosphorylated tau. In addition, cerebrovascular disease plays a profound role in AD However, it remains unknown how the amyloid-initiated processes interact with vascular pathology. Based on MRI research, the occurrence of microbleeds, present in roughly 25{4f6e60e6953937a1ab815e93856ab9862da64473b2fafe2c234a4daba9520ef4} of AD patients, is suggested to link these two phenomena. Microbleeds are related to small vessel disease and increased burden of amyloid in AD patients and may influence the blood brain barrier (BBB) function, thereby worsening disease progression. Pathological analysis now indicates that microbleeds correlate with reduced expression of BBB markers as also shown in microvessels of AD brains with amyloid deposits.

Factors involved in BBB integrity are potential diagnostic and/ or prognostic markers for AD. Furthermore, strategies to restore impaired BBB function may open up new therapeutic avenues in the treatment of AD. We recently identified that a set of ten microRNAs, small non-coding RNAs that regulate gene expression, are crucial for BBB properties and are functionally involved in its function (Reijerkerk et al., J Neurosci. conditionally accepted). Extracellular microRNAs may also circulate in blood where they are highly stable due to their packaging in so-called exosomes. These results open up the exciting prospective of using circulating microRNAs as non-invasive biomarkers for AD as well as new targets to limit occurrence of microbleeds in AD. The PhD candidate will perform innovative research from bench to bedside into novel mechanisms underlying AD and identifying associated biomarkers.

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