Towards Understanding the Roles of Heparan Sulfate Proteoglycans in Alzheimer’s Disease

Alzheimer's disease (AD) is the most common form of dementia, characterized by progressive loss of memory and cognitive dysfunctions. A central pathological event of AD is accumulation and deposition of cytotoxic amyloid- β peptide (A β ) in the brain parenchyma. Heparan sulfate proteoglycans (HSPGs) and the side chains heparan sulfate (HS) are found associated with A β deposits in the brains of AD patients and transgenic animal models of AD. A growing body of evidence from in vitro and in vivo studies suggests functional roles of HSPG/HS in A β pathogenesis. Although the question of “how and why HSPG/HS is codeposited with A β ?” still remains, it is within reach to understand the mechanisms of the events. Recent progress by immunohistochemical examination with advanced antibodies shed light on molecular structures of HS codeposited with A β . Several recent reports have provided important new insights into the roles of HSPG in A β pathogenesis. Particularly, experiments on mouse models revealed indispensible functions of HSPG in modulating A β -associated neuroinflammation and clearance of A β from the brain. Application of molecules to interfere with the interaction between HS and A β peptides has demonstrated beneficial effects on AD mouse models. Elucidating the functions of HSPG/HS in A β deposition and toxicity is leading to further understanding of the complex pathology of AD. The progress is encouraging development of new treatments for AD by targeting HS-A β interactions.