CA1 Nampt knockdown recapitulates hippocampal cognitive phenotypes in old mice which nicotinamide mononucleotide improves

Abstract

Cognitive dysfunction is one of the most concerning outcomes in global population aging. However, the mechanisms by which cognitive functions are impaired during aging remain elusive. It has been established that NAD ⁺ levels are reduced in multiple tissues and organs, including the brain. We found that NAD ⁺ levels declined in the hippocampus of mice during the course of aging, and whereas we observed minimal age-related effects on spatial learning/memory capabilities in old mice, we discovered that they developed cognitive hypersensitivity in response to aversive stimulation during contextual fear conditioning tests. This cognitive hypersensitivity appears to be associated with alterations in emotionality (fear/anxiety) and sensory processing (shock sensitivity), rather than reflect genuine conditioning/retention effects, during aging. Supplementation of nicotinamide mononucleotide (NMN) improved the sensory processing aspect of the hypersensitivity and possibly other related behaviors. Specific knockdown of nicotinamide phosphoribosyltransferase ( Nampt) in the CA1 region, but not in the dentate gyrus, recapitulates this cognitive hypersensitivity observed in old mice. We identified calcium/calmodulin-dependent serine protein kinase ( Cask) as a potential downstream effector in response to age-associated NAD ⁺ reduction in the hippocampus. Cask expression is responsive to NAD ⁺ changes and also reduced in the hippocampus during aging. Short-term NMN supplementation can enhance Cask expression in the hippocampus of old mice. Its promoter activity is regulated in a Sirt1-dependent manner. Taken together, NAD ⁺ reduction in the CA1 region contributes to development of age-associated cognitive dysfunction, aspects of which may be prevented or treated by enhancing NAD ⁺ availability through supplementation of NAD ⁺ intermediates, such as NMN.

NAD ⁺ and cognitive hypersensitivity during aging

Cognitive dysfunction is one of the most concerning outcomes in global population aging. However, the mechanisms of cognitive impairment during aging remain elusive. We found that in old mice, levels of nicotinamide adenine dinucleotide (NAD ⁺), an essential chemical for all living organisms, declined in the hippocampus, a critical part of the brain for memory and learning. We also found that age-associated hypersensitivity in cognitive and behavioral functions (cognitive hypersensitivity) was induced by reduced NAD ⁺ availability in the hippocampus. Supplementation of nicotinamide mononucleotide (NMN), a critical chemical that is converted to NAD ⁺, is able to mitigate the cognitive hypersensitivity observed in old mice. Our findings provide new insights into how NAD ⁺ decline affects age-associated anxiety/depression and how such impairments can be prevented or treated by enhancing NAD ⁺.