Alzheimer's disease (AD) is the most common cause of age-related dementia, affecting more than 25 million people worldwide. The accumulation of insoluble ß-amyloid (Aß) plaques in the brain has long been considered central to the pathogenesis of AD (green in panel to right). However, recent evidence suggests that soluble oligomeric assemblies of Aß may be of greater importance. APP processing yields Aβ monomers, which undergo oligomerization, eventually forming amyloid fibrils and plaques. Aß oligomers have been found to be potent synaptotoxins, but the mechanism by which they exert their action had remained elusive. We recently found that cellular prion protein (PrP-C) is a high-affinity receptor for Aß oligomers, mediating their toxic effects on synaptic plasticity.
Of inherited Fronto-Temporal Dementia (FTD) cases, haploinsuffiency of Progranulin is the most common etiology. TDP-43 deposition occurs in Progranulin-deficient FTD, as well as in sporadic FTD cases and in ALS. Because Progranulin is a secreted glycoprotein, we searched for high affinity receptors by expression cloning, and idenitifed Sortilin. We are now characterizing the role of PGRN/Sort1 interactions in FTD. These studies may provide an accessible cell surface approach to modify FTD and ALS progression.
The PGRN/Sort1 pathway is modified genetically by a lysosomal/endosomal protein TMEM106B in humans. We are studying the moelcualr mechanism of this regulation in cell lines and in mice.