Alzheimer's Disease–Associated Amyloid-β Precursor Protein Prevents Aging Stress–Induced Mitophagy and Fumarate Depletion to Improve Antitumor Immunity

Abstract Patients with Alzheimer's disease (AD) have a decreased incidence of cancer, with a cross-sectional analysis of a nationwide sample of adults finding 21-fold higher odds of cancer diagnosis in non-AD individuals compared with those with AD. In this study, we demonstrated that mitochondrial localization of AD-associated amyloid-β precursor protein (APP) and its cleavage product amyloid-β 40, but not mutant APP that lacks a mitochondrial localization signal, inhibits lipid stress–mediated hyperactive mitophagy in aging T cells, improving their antitumor functions. Growth of melanoma xenograft or carcinogen-induced oral cancer models was highly reduced in AD mice. Additionally, adoptive cell transfer–based immunotherapy using aging T cells isolated from AD mice suppressed tumor growth. The metabolic signature of stress-dependent mitophagy in T cells showed fumarate depletion, which was linked to decreased succination of Parkin and enhanced mitochondrial damage. Mechanistically, APP interaction with the TOMM complex at the outer mitochondrial membrane attenuated trafficking of ceramide synthase CerS6 to mitochondria in aging AD T cells, preventing ceramide-dependent mitophagy. Thus, APP restored mitochondrial fumarate metabolism and Parkin succination, improving antitumor functions of AD T cells in vitro and in vivo. Exogenous fumarate supplementation or healthy AD mitochondria transfer functionally mimicked the AD/APP phenotype in aging T cells, enhancing their antitumor activity to control tumor growth. Moreover, T cells isolated from aging donors showed elevated mitophagy with fumarate depletion, which was restored in T cells isolated from age-matched patients with AD. Together, these findings show that AD protects T cells against ceramide-dependent mitophagy and fumarate depletion to enhance antitumor functions. Significance: The reduced cancer risk in Alzheimer's disease patients is mediated by the amyloid-β 40 peptide, which inhibits aging-dependent mitophagy in T cells to improve antitumor immunity. See related commentary by Bieberich, p. 3579