Alzheimer disease (AD) is the most common cause of dementia and a leading cause of morbidity and mortality in the elderly. As life expectancy increases, the incidence of AD is expected to triple by 2050. Brain deposition of amyloid β (Aβ) plaques and neurofibrillary tangles is the pathological hallmark of AD. Late-onset AD (diagnosed at ≥ 65 years of age) constitutes > 99% of cases; however, its pathological mechanisms are unknown. Recently, Liu et al1 developed a novel animal model to interrogate the interaction between neuronal heparan sulfate (HS) proteoglycans (HSPGs) and Aβ plaques and discovered important insights into the pathological mechanism of AD. New insights generated from research on this HS-deficient model may shed light on potential strategies to treat late-onset AD.
HSPGs consist of HS chains covalently linked to a protein core. They are expressed in virtually all mammalian cell types and play important roles in cell proliferation, homeostasis, and embryonic development. The EXT1 family of enzymes performs a critical step of HSPG biosynthesis by catalyzing the elongation of alternating polysaccharides of N-acetylglucosamine and glucuronic acid. Liu et al generated a mouse model, amyloid precursor protein/nExt1conditional knockout (APP/PS1; nExt1CKO), that conditionally reduces Ext1 expression in adult cortex and hippocampus and bypasses the deleterious effects of decreased Ext1 expression in embryonic brains. Immunostaining with an anti-Aβ antibody revealed that Aβ burden in the cortex and hippocampus of APP/PS1; nExt1CKO mice at 12 months of age was one-third of the control group’s (APP/PS1’s) burden (Figure). Additional analysis revealed that HS colocalized with Congo red–positive amyloid plaques. The ratio of oligomeric Aβ to total Aβ in APP/PS1; nExt1CKO was significantly decreased compared with the control mice, suggesting that HS deficiency reduced the level of the deleterious, AD-associated oligomeric Aβ.
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