Dopamine neurons in a part of the brain called the midbrain may, with aging, be increasingly susceptible to a vicious spiral of decline driven by fuel shortages, according to a study led by Weill Cornell Medicine investigators. The findings offer a potential explanation for the degeneration of this neuron population in Parkinson’s disease.

In the study, published Dec. 5 in the Proceedings of the National Academy of Sciences, the scientists examined how midbrain dopamine neurons, which have unusually numerous output branches, handle their high energy requirements. They showed that these neurons under normal conditions create a fuel reserve in the form of clusters of glucose molecules called glycogen. This allows the neurons to keep working for a surprisingly long time even when their usual supply of glucose from the blood is interrupted. However, the researchers also discovered that the neurons regulate their glycogen storage in a way that can leave them highly vulnerable to glucose shortages, especially as their functions begin to decline with aging.

“This vulnerability may explain the deaths of these midbrain neurons in Parkinson’s and is consistent with the idea that energy insufficiency is a common failure mode in neurological disorders,” said study senior author Timothy Ryan, the Tri-Institutional Professor of Biochemistry and Biophysics and a professor of biochemistry in anesthesiology at Weill Cornell Medicine.

How DAP12 deletion enhances brain resilience in female tauopathy mice.

Microglia selectively expresses DAP12 (DNAX-activation protein 12), which, plays a crucial role in microglial immune responses.

Previously, it was show that tauopathy mice lacking DAP12 exhibit higher tau pathology but are protected from tau pathology-induced cognitive deficits but the mechanism remains elusive.

The authors in this study show that tau processing in primary microglia is reduced by Dap12 deletion, while, tau pathology increased in female tauopathy mice, with minimal effects on males. However, brain inflammation, synapse loss, and demyelination are reduced by Dap12 deletion indicating enhanced resilience to tau toxicity.

The authors also show that elevated SLIT2 levels and demyelination in tauopathy and is reversed by Dap12 deletion. The author s also found correlation of SLIT2 expression and tau pathology in AD brain tissue. https://sciencemission.com/DAP12-deletion-reduces-neuronal-SLIT2

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Background Pathogenic tau accumulation drives neurodegeneration in Alzheimer’s disease (AD). Enhancing the aging brain’s resilience to tau pathology would lead to novel therapeutic strategies. DAP12 (DNAX-activation protein 12), highly and selectively expressed by microglia, plays a crucial role in microglial immune responses. Previous studies have shown that tauopathy mice lacking DAP12 exhibit higher tau pathology but are protected from tau pathology-induced cognitive deficits. However, the exact mechanism behind this resilience remains elusive. Methods We investigated the effects of DAP12 deletion on tau pathology, as well as tau-induced brain inflammation and neurodegeneration, in homozygous human Tau P301S transgenic mice. In addition, we conducted single-nucleus RNA sequencing of hippocampal tissues to examine cell type-specific transcriptomic changes at the single-cell level.