Glycolysis-enhancing alpha 1-adrenergic antagonists are neuroprotective in Alzheimers disease

Zhang, Q.; Schultz, J.; Simmering, J.; Kirkpatrick, B. Q.; Weber, M. A.; Skuodas, S.; Hicks, T.; Pierce, G.; Laughlin, M.; Bertolli, A. X.; Larson, T.; Thangavel, R.; Oya, M.; Meyerholz, D.; Aldridge, G.; Fassler, J.; Narayanan, N. S.

doi:10.1101/2025.04.03.647018

bioRxiv · 10.1101/2025.04.03.647018

Glycolysis-enhancing alpha 1-adrenergic antagonists are neuroprotective in Alzheimers disease

Zhang, Q.·Schultz, J.·Simmering, J.·Kirkpatrick, B. Q.·Weber, M. A.·Skuodas, S.·Hicks, T.·Pierce, G.·Laughlin, M.·Bertolli, A. X.·Larson, T.·Thangavel, R.·Oya, M.·Meyerholz, D.·Aldridge, G.·Fassler, J.·Narayanan, N. S.

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Abstract

Terazosin (TZ) is an 1-adrenergic receptor antagonist that enhances glycolysis by activating the enzyme phosphoglycerate kinase 1 (PGK1). Epidemiological data suggest that TZ may be neuroprotective in Parkinsons disease and in dementia with Lewy bodies and that glycolysis-enhancing drugs might be protective in other neurodegenerative diseases involving protein aggregation, such as Alzheimers disease (AD). We investigated TZ in AD and report four main results. First, we found that TZ increased ATP levels in a Saccharomyces cerevisiae mutant with impaired energy homeostasis and reduced the aggregation of the AD-associated protein, amyloid beta (A{beta}) 42. Second, in an AD transgenic mouse model (5xFAD) we found that TZ attenuated amyloid pathology in the hippocampus and rescued cognitive impairments in spatial memory and interval timing behavioral assays. Third, using the Alzheimers Disease Neuroimaging Initiative (ADNI) database, we found that AD patients newly started on TZ or related glycolysis-enhancing drugs had a slower progression of both cognitive dysfunction and neuroimaging biomarkers, such as 18F-fluorodeoxyglucose positron emission tomography (FDG-PET), a measure of brain metabolism. Finally, in a large human administrative dataset, we found that patients taking TZ or related glycolysis-enhancing drugs had a lower hazard of being diagnosed with AD compared to those taking tamsulosin or 5-alpha reductase inhibitors. These data further implicate metabolism in neurodegenerative diseases and suggest that glycolysis-enhancing drugs may be neuroprotective in AD.

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Zhang, Q., Schultz, J., Simmering, J., Kirkpatrick, B. Q., Weber, M. A., Skuodas, S., Hicks, T., Pierce, G., Laughlin, M., Bertolli, A. X., Larson, T., Thangavel, R., Oya, M., Meyerholz, D., Aldridge, G., Fassler, J., Narayanan, N. S.. 2025-04-03. Glycolysis-enhancing alpha 1-adrenergic antagonists are neuroprotective in Alzheimers disease. https://doi.org/10.1101/2025.04.03.647018

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