Journal Article

DZNE-2026-00651

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Lactate treatment improves brain biochemistry and cognitive function in transgenic Alzheimer's and wild-type mice.

Belhaj, I. ; Åmellem, I. ; Tartanoglu, C. H.DZNE* ; Weidemann, H. M. ; Vallenari, E. M. ; Yang, M. ; Chaudhry, F. A. ; Bjørås, M. ; Storm-Mathisen, J. ; Bergersen, L. H.

2026
Springer Nature [London]

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Please use a persistent id in citations: doi:10.1038/s41598-026-48154-6

Abstract: Lactate, a well-known metabolite and signalling molecule, holds therapeutic potential for neurodegenerative diseases. Here, we investigated the effects of chronic lactate treatment on cognition and molecular biomarkers in the 5XFAD mouse model of Alzheimer’s disease (AD) and in wild-type (WT) controls using behavioural testing alongside proteomic and transcriptomic analyses. Mice received lactate or vehicle injections 4 days per week for 11 weeks, with behavioural testing before and after the treatment period. Lactate improved working memory in late-treated AD mice, without eliciting anxiety-like behaviour. At the molecular level, lactate reduced Il1b expression, and in a sex-dependent manner, normalised NEFL, and enhanced synaptic integrity proteins (OPCML, PPFIA2, STXBP3, SYT1, VGLUT2, VSNL1) in AD mice, while also augmenting mitochondrial regulators (ATP5G2, GRPEL1, SLC25A23) across genotypes. Notably, lactate upregulated low-abundance ionotropic glutamate receptor mRNAs (Grik3, Grin2c, Grid2ip) in female AD mice, indicating enhanced glutamatergic signalling. In WT mice, lactate increased expression of neurotrophic factors (Bdnf, Igf1, Vegfa), anti-inflammatory cytokines (Il4 and Il13), and the neuronal lactate transporter Mct2, suggesting promoted neuronal resilience. Together, these findings indicate that lactate treatment can mitigate cognitive decline and enhance molecular pathways of resilience in AD, warranting larger, age-stratified studies to validate its therapeutic potential and elucidate underlying mechanisms.The online version contains supplementary material available at 10.1038/s41598-026-48154-6.

Keyword(s): 5XFAD ; Alzheimer’s disease ; Glutamate receptors ; Growth factors ; Lactate ; Neuroinflammation

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Contributing Institute(s):

1. Cellular Circuits of Memory (AG Viana-da-Silva)

Research Program(s):

1. 351 - Brain Function (POF4-351) (POF4-351)

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