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Alpha-ketoglutarate mitigates insulin resistance and metabolic inflexibility in a mouse model of Ataxia-Telangiectasia

Insulin-activated ataxia-telangiectasia mutated (ATM) regulates glucose metabolism. Here the authors report that its disruption in a mouse model of ataxia-telangiectasia leads to insulin resistance, glutamine dependence, and selective Purkinje cell degeneration, while α-Ketoglutarate supplementation shows promise in mitigating neurodegeneration.

Jacquelyne Ka-Li Sun
Ronald P. Hart
Kim Hei-Man Chow
ResearchOpen Access21 Oct 2025
Nature Communications

Volume: 16, P: 1-27
Perimenopausal state oestradiol to progesterone imbalance drives Alzheimer’s risk via ERRα dysregulation and energy dyshomeostasis

Low progesterone-to-oestradiol ratio during perimenopause increases Alzheimer’s disease (AD) risk by disrupting ERRα, hence impairing neuronal cholesterol and energy balance. ERRα is a key regulator linking peripheral hormonal changes to female-biased AD susceptibility.

Jacquelyne Ka-Li Sun
Amy Zexuan Peng
Kim Hei-Man Chow
ResearchOpen Access22 Nov 2025
Nature Communications

Volume: 16, P: 1-27
Microglial hexokinase 2 deficiency increases ATP generation through lipid metabolism leading to β-amyloid clearance

Accumulation of β-amyloid plaques contributes to neuronal cell death in Alzheimer’s disease. In this study, Leng et al. describe a role for hexokinase 2 in metabolic reconfiguration in microglia that promotes phagocytosis and supports amyloid plaque clearance.

Lige Leng
Ziqi Yuan
Jie Zhang
Research06 Oct 2022
Nature Metabolism

Volume: 4, P: 1287-1305
Loopholes in the DNA contract kill neurons

Hexanucleotide repeat expansions in C9orf72 gene locus create double jeopardy, first by leading to DNA–RNA R-loops that spawn double-strand breaks and second by the synthesis of dipeptide repeats that hinder DNA repair. This two-pronged mechanism may explain neurodegeneration in amyotrophic lateral sclerosis and frontotemporal dementia.

Karl Herrup
Kai-Hei Tse
Hei-Man Chow
News & Views01 Sept 2017
Nature Neuroscience

Volume: 20, P: 1192-1194
Author Correction: Microglial hexokinase 2 deficiency increases ATP generation through lipid metabolism leading to β-amyloid clearance

Lige Leng
Ziqi Yuan
Jie Zhang
Amendments and Corrections14 Oct 2022
Nature Metabolism

Volume: 4, P: 1420
Mutant huntingtin induces neuronal apoptosis via derepressing the non-canonical poly(A) polymerase PAPD5

PAPD5 is responsible for adenylation of microRNAs. Here, the authors show that elevated level of PAPD5 enhances the adenylation and reduced expression of miR-7-5p. As a result, expression of TAB2, a target of miR-7-5p, is induced triggering neuronal apoptosis in Huntington’s disease.

Zhefan Stephen Chen
Shaohong Isaac Peng
Ho Yin Edwin Chan
ResearchOpen Access09 Apr 2025
Nature Communications

Volume: 16, P: 1-18
Age-related hyperinsulinemia leads to insulin resistance in neurons and cell-cycle-induced senescence

Chow et al. show that high blood levels of insulin in prediabetic conditions are linked to saturated insulin levels in the brain. Chronic insulin exposure leads to insulin resistance, cell cycle reentry and premature aging, corresponding to senescence-like pathological changes in neurons.

Hei-Man Chow
Meng Shi
Karl Herrup
Research21 Oct 2019
Nature Neuroscience

Volume: 22, P: 1806-1819
Genomic integrity and the ageing brain

Ageing leads to the gradual loss of brain function and is a key risk factor for most late-onset neurological disease. In this Review, Chow and Herrup explore how the loss of DNA integrity drives brain ageing and contributes to the pathogenesis of many seemingly unrelated conditions.

Hei-man Chow
Karl Herrup
Reviews14 Oct 2015
Nature Reviews Neuroscience

Volume: 16, P: 672-684

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