Heparan sulfate proteoglycan in Alzheimer’s disease: aberrant expression and functions in molecular pathways related to amyloid-β metabolism

Alzheimer's disease (AD) is the most common form of dementia. Currently, there is no effective treatment for AD, as its etiology remains poorly understood. Mounting evidence suggests that the accumulation and aggregation of amyloid-β peptides (Aβ), which constitute amyloid plaques in the brain, is critical for initiating and accelerating AD pathogenesis. Considerable efforts have been dedicated to shedding light on the molecular basis and fundamental origins of the impaired Aβ metabolism in AD. Heparan sulfate (HS), a linear polysaccharide of the glycosaminoglycan family, co-deposits with Aβ in plaques in the AD brain, directly binds and accelerates Aβ aggregation, and mediates Aβ internalization and cytotoxicity. Mouse model studies demonstrate that HS regulates Aβ clearance and neuroinflammation in vivo. Previous reviews have extensively explored these discoveries. Here, this review focuses on the recent advancements in understanding abnormal HS expression in the AD brain, the structural aspects of HS-Aβ interaction, and the molecules involved in modulating Aβ metabolism through HS interaction. Furthermore, this review presents a perspective on the potential effects of abnormal HS expression on Aβ metabolism and AD pathogenesis. In addition, the review highlights the importance of conducting further research to differentiate the spatiotemporal components of HS structure and function in the brain and AD pathogenesis.