Rapamycin and Alzheimer disease: a hypothesis for the effective use of rapamycin for treatment of neurodegenerative disease

Abstract

In 2019 we summarized work relating to the potential use of rapamycin for treating Alzheimer disease (AD). We considered the commentary necessary because use of rapamycin in people with AD is a very real prospect and we wanted to present a balanced view of the likely consequences of MTOR (mechanistic target of rapamycin kinase) inhibition in the AD brain. We concluded that use of rapamycin, an MTOR inhibitor that increases macroautophagy/autophagy, could hold promise for prevention of AD if used early enough. However, MTOR inhibition appeared ineffectual in resolving existing amyloid pathology in AD mouse models. In this View article, we update these observations with new studies that have used rapamycin in AD models and provide evidence both for and against its use in AD. We also discuss rapamycin in the light of new research that describes rapamycin-induced autophagic stress in the aging brain and autophagic stress as the origin of the amyloid plaque itself. We conclude that rapamycin will have complex effects on the brain in AD. Further, we hypothesize that lysosomal degradative capacity in the brain will likely determine how effective or detrimental rapamycin will be as a treatment of AD.Abbreviations: AD: Alzheimer disease; APP: amyloid beta precursor protein; MAPT/tau: microtubule associated protein tau; MTOR: mechanistic target of rapamycin kinase; MTORC1: mechanistic target of rapamycin kinase complex 1.

Keywords: Alzheimer disease; autophagy; dementia; lysosome; rapamycin.

Figure 1.

Lysosomal degradative potential and its interaction with AD and rapamycin – a hypothesis. (A) In a normal brain, autophagy is resolved by efficient lysosomes. (B) In AD, lysosomes have reduced degradative potential and autophagic material accumulates. (C) Recent work has shown that rapamycin can reduce amyloid plaque burden after plaques are established. We hypothesize this is because there is some lysosomal degradative potential in the system that can process increased autophagic flux stimulated by rapamycin. (D) In contrast, the failure of rapamycin to decrease amyloid plaques in recent papers that have used the 5XFAD mouse model could reflect lower lysosomal degradative potential.