New Insights into Alzheimer’s Disease: Novel Pathogenesis, Drug Target and Delivery

作者：Haishu Chen, Jinan Xu, Hanyuan Xu, Tiancheng Luo, Yihao Li, Ke Jiang, Yangping Shentu, Zhiqian Tong · 发表于：Pharmaceutics · 年份：2023 · DOI：10.3390/pharmaceutics15041133 · 被引用次数：15 · 研究领域：Alzheimer's disease research and treatments、Prion Diseases and Protein Misfolding、Dementia and Cognitive Impairment Research

Alzheimer's disease (AD), the most common type of dementia, is characterized by senile plaques composed of amyloid β protein (Aβ) and neurofilament tangles derived from the hyperphosphorylation of tau protein. However, the developed medicines targeting Aβ and tau have not obtained ideal clinical efficacy, which raises a challenge to the hypothesis that AD is Aβ cascade-induced. A critical problem of AD pathogenesis is which endogenous factor induces Aβ aggregation and tau phosphorylation. Recently, age-associated endogenous formaldehyde has been suggested to be a direct trigger for Aβ- and tau-related pathology. Another key issue is whether or not AD drugs are successfully delivered to the damaged neurons. Both the blood-brain barrier (BBB) and extracellular space (ECS) are the barriers for drug delivery. Unexpectedly, Aβ-related SP deposition in ECS slows down or stops interstitial fluid drainage in AD, which is the direct reason for drug delivery failure. Here, we propose a new pathogenesis and perspectives on the direction of AD drug development and drug delivery: (1) aging-related formaldehyde is a direct trigger for Aβ assembly and tau hyperphosphorylation, and the new target for AD therapy is formaldehyde; (2) nano-packaging and physical therapy may be the promising strategy for increasing BBB permeability and accelerating interstitial fluid drainage.