Zengeler, K. E. | bioRxiv Science

bioRxiv2024

Mitochondrial NADK2-dependent NADPH controls Tau oligomer uptake in human neurons

Alterations in NADH and NADPH metabolism are associated with aging, cancer, and Alzheimers Disease. Using 2P-FLIM imaging of the mitochondrial NAD(P)H in live human neurons and PS19 mouse brains, we show that tau oligomers (TauO) upregulate the mitochondrial de novo NADPH synthesis through NADK2. This process controls LRP1-mediated internalization of TauO, setting a vicious cycle for further TauO internalization. Thus, mitochondrial NADK2-dependent NADPH controls a key step in TauO toxicity.

neuroscience↗

bioRxiv2019

Tet2 negatively regulates memory fidelity

Despite being fully differentiated, DNA methylation is dynamically regulated in post-mitotic glutamatergic neurons in the CA1 of the hippocampus through competing active DNA methylation and de-methylation, a process that regulates neuronal plasticity. Active DNA methylation after learning is necessary for long-term memory formation, and active DNA de-methylation by the TET enzymes has been implicated as a counter-regulator of that biochemical process. We demonstrate that Tet2 functions in the CA1 as a negative regulator of long-term memory, whereby its knockdown across the CA1 or haploinsufficiency in glutamatergic neurons enhances the fidelity of hippocampal-dependent spatial and associative memory. Loci of altered DNA methylation were then determined using whole genome bisulfite sequencing from glutamatergic Tet2 haploinsufficient CA1 tissue, which revealed hypermethylation in the promoters of genes known to be transcriptionally regulated after experiential learning. This study demonstrates a link between Tet2 activity at genes important for memory formation in CA1 glutamatergic neurons and memory fidelity.

neuroscience↗