Natalia V. Oleinik

Mechanisms linking amyloid peptides to mitochondrial dysfunction and impaired mitophagy in Alzheimer’s disease (AD) remain poorly defined. Here, we report that, in healthy aging neurons, mitochondrial ceramide synthase 1 (CerS1) localization accompanies increased mitochondrial C18-ceramide and mitophagy in damaged mitochondria. In neuronal, mouse, and human AD tissues, amyloid precursor protein (APP) or Aβ40, but not Aβ42, shows increased proximity or co-association with TOM20/TOM40 alongside reduced mitochondrial CerS1/C18-ceramide accumulation and mitophagy. Mitochondria-excluded mutant APP does not reproduce these responses in neuronal cells. WT-APP expression is associated with reduced p17/PERMIT–ICT1 proximity, which does not establish direct APP–ICT1 binding or disruption of complex formation. Reduced mitophagy also accompanies lysosomal Aβ42 accumulation and secretion from neurons. Aged CerS1top/top mice, expressing catalytically inactive CerS1, exhibit mitochondrial dysfunction, behavioral deficits, and amyloid-positive plaque accumulation. Treatment with the peptide-targeted nanoparticle Pen-Cera-LCL768, which accumulates in the brain after intranasal administration, increases mitophagy-related readouts, reduces plaque burden, and improves behavioral performance in aged 3xTg and CerS1top/top mice. Mdivi-1 attenuates treatment effects in 3xTg mice, but its lack of specificity limits conclusions about mitophagy dependence.

The article presents the results of a study on a higher education financing policy implemented by the state government of Santa Catarina in 2023, called the “Programa Universidade Gratuita” (PUG). The study aimed to analyze “whether” and “how” the regulatory frameworks of this policy altered the public financing regime for research and extension activities in higher education institutions in Santa Catarina. More specifically, the research sought to understand the importance and the role that research and extension occupy in the PUG. This is a qualitative, exploratory study, involving document collection and content analysis. The scope of the research includes Complementary Law No. 831, dated July 31, 2023, and Decree No. 219, dated August 2, 2023. The results indicate that the PUG is a policy for entry and permanence in higher education. However, unlike the previous Uniedu program, its implementation has not effectively involved research and extension as formative conditions. Thus, although the purpose of the Free University Program stems from a financial assistance policy aimed at facilitating access and permanence for young people in Santa Catarina, its focus has become largely centered on teaching. Therefore, it is necessary to provide scholarships for students to conduct research and participate in extension projects at the universities that join the program.

List of diagnostic codes for cancer ascertainment in the Medical Expenditure Panel Survey.

This file contains a key resources table that includes details of key experimental materials and supplies used in this study.

Metabolic changes in old WT T-cells as measured by flux metabolomics.

Different therapeutic approaches utilizing the superiority of 3xTg T-cells in resisting tumor growth and progression.

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

ATAD3 shuttles CerS6 to the mitochondria of aging T-cells and mitochondrial APP blocks this effect.

T-cells from human AD patients with cancer show an increase in APP levels, a decrease in mitophagy, and an increase in cytokine production.

Demographic characteristics of human APP-high vs APP-low samples.