Mitophagy and NAD⁺ inhibit Alzheimer disease

ABSTRACT

Our latest publication on the inhibition of Alzheimer disease (AD) through mitophagy consolidates the ‘defective mitophagy hypothesis of AD etiology’. Dementia (majorly AD) affects over 50 million people worldwide, and for AD there is no cure. AD leads to progressive loss of cognition, and pathological hallmarks of AD include aggregates of amyloid-β peptides extracellularly and MAPT (microtubule associated protein tau) intracellularly. However, there is no conclusive link between these pathological markers and cognitive symptoms. Anti-AD drug candidates have repeatedly failed, which led us to investigate other molecular etiologies to guide drug development. Mitochondria produce the majority of cellular ATP, affect Ca²⁺ and redox signaling, and promote developmental and synaptic plasticity. Mitochondrial dysfunction and accumulation of damaged mitochondria are common in brain tissues from AD patients and transgenic AD animal models, but the underlying molecular mechanisms are not fully understood. Damaged mitochondria are removed through multiple pathways, the major 2 being mitophagy and the ubiquitin proteasome pathway. Mitophagy is essential for clearance of damaged mitochondria to maintain mitochondrial homeostasis, ATP production, and neuronal activity and survival. These pieces of evidence converge on the ‘defective mitophagy hypothesis of AD etiology’, and the current cross-species study provides strong support for this hypothesis.

KEYWORDS:

• Mitophagy
• mitochondria
• Alzheimer’s disease
• aging
• memory

Acknowledgments

I acknowledge the invaluable collaborations and continued supports from Drs. Vilhelm Bohr, Mark P. Mattson, Nektarios Tavernarakis, M. Zameel Cader, and Hilde Nilsen. I appreciate Dr. Yujun Hou, Dr. Konstantinos Palikaras, and all the other co-authors for all their contributions in the current study. I thank Jesse Keer for reading the manuscript. I am grateful for the generous support from the HELSE SøR-ØST (E.F.F., #2017056), the Research Council of Norway (E.F.F., #262175 and #277813), and an Akershus University Hospital Strategic grant (E.F.F., #269901). The Fang group has CRODA with Chromadex. This ´autophagic puncta´ was written based on our recent publication and several major findings from other research papers. I was unable to cite these references due to the one citation limitation of this ´autophagic puncta´.

Disclosure statement

E.F.F. has  Cooperative Research and Development Agreement (CRADA) arrangement with ChromaDex.

Additional information

Funding

This work was supported by the Helse Sør-Øst RHF [017056]; Norges Forskningsråd [#262175 and #277813].