Neurotrophic Mechanisms in the Adult Nervous System – Vascular dementia and Alzheimer’s Disease

An unwanted outcome of increased life expectancy in modern societies is the growing prevalence of age-associated diseases. Among these, dementia is one of the biggest unmet healthcare needs globally.

Alzheimer’s disease (AD) and vascular dementia (VaD) are the two major causes of dementia and both diseases are age-related.

The continuing failures in AD treatment trials constitute stark reminders that our understanding of the basic biology of these types of diseases is far from complete and will require more study at the fundamental level.

Neurotrophic mechanisms are critical for the generation, survival and connectivity of neurons, and are also expressed in the context of neural injury and neurodegeneration.

Our research group has initiated investigations aimed at elucidating the contribution of two major neurotrophic receptors, the death receptor p75NTR and the receptor tyrosine kinase TrkB, to pathophysiological processes underlying AD and VaD, respectively. Our preliminary studies led to several unexpected discoveries, forming the basis of this proposal.

We will study the role of TrkB in pericytes of the brain vasculature, as our studies suggest that it is induced by brain hypoperfusion and contributes to the integrity of the brain blood vessels.

We will study how p75NTR is able to regulate internalization and amyloidogenic processing of APP, and we will provide proof of principle evidence that inactivation of p75NTR late in the course of AD has beneficial benefits.