Chapter 14 - Drug discovery in Alzheimer’s disease by regulating autophagy

Elsevier, Autophagy Dysfunction in Alzheimer's Disease and Dementia, First Edition, 2022, pp 263-290
Hamano T., Endo Y.

Neurofibrillary tangles that are composed of extensively phosphorylated tau protein and senile plaques (SPs), which consists of amyloid β protein (Aβ), are pathological hallmarks of Alzheimer’s disease (AD). Many autophagic vacuoles are found in swollen axons around SPs in the AD brain. This suggested that autophagy is impaired in AD brain. Previous studies revealed that Aβ and tau are degraded by autophagy. Autophagy regulation may therefore be a therapeutic strategy for AD. Thus far, as autophagy modulators, the mTOCR inhibitor rapamycin and its analogs, other mTORC inhibitors, such as methylene blue and curcumin, the AMPK activators metformin, trehalose, and resveratrol, IMPase inhibitor lithium, and TFEB activators have been proposed. Some of these drugs were examined in phase II or phase III clinical trials. However, as caspase activation by autophagy activation was also reported, precise autophagy regulation is essential for the treatment of AD.