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

Abstract

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.