Glycosaminoglycan Modulation of Cathepsin D in the context of Alzheimer’s Disease

Abstract

Alzheimer’s Disease (AD) is a chronic neurodegenerative disorder, and the most common form of dementia, characterized by a loss in memory and other cognitive abilities presenting with extensive neuronal loss, amyloid plaques, and neurofibrillary tangles. Cathepsin D (CatD) is a lysosomal aspartyl protease that has been shown to break down these aberrantly formed proteins. Physiologic modulators of this clearance mechanism, which could herald a new era of AD therapeutics, remain poorly studied. One type of modulator known to date is the family of glycosaminoglycans (GAGs). Here, we study a range of natural and unnatural GAGs of varying chain lengths and sulfation levels to comprehensively understand GAG modulation of both zymogenic form of CatD (z-CatD) and mature- CatD (m-CatD). Using computational studies, we show the unique structures of z-CatD and m-CatD endows both proteins with the ability to bind preferentially to distinct sulfated GAGs at one of the two putative sites of binding. Enzyme kinetics shows that both the z-CatD and m-CatD are activated at low GAG levels, whereas higher levels induce inhibition. Interestingly, the extent of activation is dependent on the type of GAG as well as the form of CatD. Together, these studies reveal that the higher affinity site corresponds to activation, whereas the lower affinity site corresponding to inhibition. Overall, the phenomenon of GAG-concentration dependent dual modulation of CatD (activation and inhibition) presents a very interesting molecular regulatory mechanism with possible consequences in clearance of plaques and tangles