Central nervous system sulfatide deficiency as a causal factor for bladder disorder in Alzheimer's disease

Abstract

Background Despite being a brain disorder, Alzheimer's disease (AD) is often accompanied by peripheral organ dysregulations (e.g., loss of bladder control in late‐stage AD), which highly rely on spinal cord coordination. However, the causal factor(s) for peripheral organ dysregulation in AD remain elusive. Methods The central nervous system (CNS) is enriched in lipids. We applied quantitative shotgun lipidomics to determine lipid profiles of human AD spinal cord tissues. Additionally, a CNS sulfatide (ST)‐deficient mouse model was used to study the lipidome, transcriptome and peripheral organ phenotypes of ST loss. Results We observed marked myelin lipid reduction in the spinal cord of AD subjects versus cognitively normal individuals. Among which, levels of ST, a myelin‐enriched lipid class, were strongly and negatively associated with the severity of AD. A CNS myelin‐specific ST‐deficient mouse model was used to further identify the causes and consequences of spinal cord lipidome changes. Interestingly, ST deficiency led to spinal cord lipidome and transcriptome profiles highly resembling those observed in AD, characterized by decline of multiple myelin‐enriched lipid classes and enhanced inflammatory responses, respectively. These changes significantly disrupted spinal cord function and led to substantial enlargement of urinary bladder in ST‐deficient mice. Conclusions Our study identified CNS ST deficiency as a causal factor for AD‐like lipid dysregulation, inflammation response and ultimately the development of bladder disorders. Targeting to maintain ST levels may serve as a promising strategy for the prevention and treatment of AD‐related peripheral disorders.

Increased risk of osteoporosis in patients with cognitive impairment: a systematic review and meta-analysis

“…Neurodegenerative disorders, such as Alzheimer’s disease (AD), Parkinson’s disease, and amyotrophic lateral sclerosis, are characterized by the progressive degeneration of neurons in the central nervous system. Numerous studies have extensively investigated the contribution of neurodegenerative disorders in various peripheral disorders [ 6 – 10 ]. Moreover, these neurodegenerative disorders can have adverse effects on bone health.…”

The impact of sulfatide loss on the progress of Alzheimer's disease

“…Using shotgun lipidomics, the authors have pinpointed a decrease in the overall lipid content within the spinal cords of AD individuals when compared to the lipid composition observed in the spinal cords of those with normal cognitive function. 11 The impact of these changes was more pronounced in white matter compared to grey matter. The reduction in ST levels within myelin lipids extracted from AD patients was remarkable and displayed a correlation with increased severity of tau-associated AD pathology.…”

“…In a recent publication by Xianlin Han and his team, new insights into the impact of ST loss on the progression of AD have emerged. Using shotgun lipidomics, the authors have pinpointed a decrease in the overall lipid content within the spinal cords of AD individuals when compared to the lipid composition observed in the spinal cords of those with normal cognitive function 11 . The impact of these changes was more pronounced in white matter compared to grey matter.…”