UCSF

At present, there are no means to counter functional loss in the aging brain underlying both normal cognitive decline and dementia-related neurodegenerative disease in the elderly. As such, defining key regulatory molecular signatures in the aging brain associated with age-related functional decline may help identify potential targets to restore cognition at old age. Given onset of cognitive impairments is not uniform across cognitive modalities, we sought to delineate the ages at which individual learning and memory processes exhibit dynamic deterioration. To define the temporal kinetics of age-related cognitive decline, we first assessed hippocampal-dependent learning and memory in the mouse species across the lifespan at young (3 months), mature (6 months), middle-aged (12 months), aged (18 months) and old (24 months) ages. We observed that the rate of cognitive decline was indeed different across distinct types of learning and memory, with recognition and associative memory impairments occurring at faster kinetics compared to spatial and working memory deficits. Young mice outperformed all age groups in recognition and associative memory, while mice that were middle-aged performed comparable to younger groups in spatial memory and working memory tasks. To define molecular changes associated with age-related cognitive decline, we performed single nucleus RNA sequencing (snRNA seq) and single nucleus chromatin accessibility sequencing (snATAC-seq) on hippocampi from young and aged mice and characterized differences in cell-type specific gene expression patterns and DNA regulatory elements during aging. DNA methylation has emerged as a critical modulator of neuronal plasticity and cognitive function. Notwithstanding, the role of enzymes that demethylate DNA remain to be fully explored. Here, we report that loss of ten-eleven translocation methylcytosine dioxygenase 2 (Tet2), which catalyzes oxidation of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC), in adult neurons enhances cognitive function. In the adult mouse hippocampus, we detected an enrichment of Tet2 in neurons. Viral-mediated neuronal overexpression and RNA interference of Tet2 altered dendritic complexity and synaptic-plasticity-related gene expression in vitro. Overexpression of neuronal Tet2 in adult hippocampus, and loss of Tet2 in adult glutamatergic neurons, resulted in differential hydroxymethylation associated with genes involved in synaptic transmission. Functionally, overexpression of neuronal Tet2 impaired hippocampal-dependent memory, while loss of neuronal Tet2 enhanced memory. Ultimately, these data identify neuronal Tet2 as a molecular target to boost cognitive function.