Rapamycin and Alzheimer disease: a double-edged sword?

Abstract

Numerous studies have reported that inhibition of MTOR (mechanistic target of rapamycin kinase) clearly reduces Alzheimer disease neuropathological hallmarks in mouse models. This has resulted in calls for the use of the MTOR inhibitor rapamycin for the treatment of dementia in humans. Unfortunately, intervention with rapamycin in these mouse studies commenced before or early in the appearance of these pathological hallmarks. Later in Alzheimer disease, when dementia actually manifests, the brain's lysosomal system is severely damaged and treatment with rapamycin is likely to exacerbate this damage. We reassess literature described by a recent perspective article calling for the use of MTOR inhibition in dementia and conclude that rapamycin could be useful, but only in people who are in the earliest stages of Alzheimer disease. We contend that our interpretation of preclinical data concerning use of rapamycin in Alzheimer disease models is necessary if we are to avoid another failed Alzheimer disease drug trial. Abbreviations: AD: Alzheimer disease; APP: amyloid beta precursor protein; MAPT: 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.

Treatment of advanced AD with rapamycin. (A) In Alzheimer disease, lysosomal-system cargo (yellow vesicles) that should be retrogradely transported up an axon (green) to the soma, where lysosomal degradation occurs, accumulate because lysosomal function is critically damaged. (B) Treatment with rapamycin enhances the generation of lysosomal-system cargo, and during AD this will result in further accumulation of lysosomal vesicles. According to the literature this may promote propagation of MAPT aggregates to another neuron (red), and further production of amyloid plaques. *How release of amyloid-β from the dystrophy occurs is poorly understood but could happen by fusion of lysosomal-system cargo with the axon’s plasma membrane, or rupture of this membrane and release of lysosomal-system contents into the parenchyma.