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University of Toronto

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Biomaterials, Jan 24 2025, 318 S0142-9612(25)00061-4 | https://doi.org/10.1016/j.biomaterials.2025.123142 Brain microenvironment-remodeling nanomedicine improves cerebral glucose metabolism, mitochondrial activity and synaptic function in a mouse model of Alzheimer's disease

Elliya Park ^a, Chunsheng He ^a, Azhar Z. Abbasi ^a, Meng Tian ^b, Shudi Huang ^a, Liting Wang ^a, John Georgiou ^c, Graham L. Collingridge^b,c, Paul E. Fraser ^d, Jeffrey T. Henderson ^a, Xiao Yu Wu ^a

^a144 College St, Leslie Dan Faculty of Pharmacy, University of Toronto, Toronto, ON, M5S 3M2, Canada
^b135 Nassau St, TANZ Centre for Research in Neurodegenerative Diseases, University of Toronto, Toronto, ON, M5T 1M8, Canada
^c600 University Ave, Lunenfeld-Tanenbaum Research Institute, Mount Sinai Hospital, Toronto, ON, M5G 1X5, Canada
^d60 Leonard Ave, Tanz Centre for Research in Neurodegenerative Diseases, Department of Medical Biophysics, University of Toronto, Toronto, ON, M5T 2S8, Canada

Corresponding author : Xiao Yu Wu

Abstract

The development of disease-modifying therapeutics for Alzheimer's disease remains challenging due to the complex pathology and the presence of the blood-brain barrier. Previously we have described the investigation of a brain-penetrating multifunctional bioreactive nanoparticle system capable of remodeling the hypoxic and inflammatory brain microenvironment and reducing beta-amyloid plaques improving cognitive function in a mouse model of Alzheimer's disease. Despite the linkage of hypoxia and inflammation to metabolic alteration, the effects of this system on modulating cerebral glucose metabolism, mitochondrial activity and synaptic function remained to be elucidated. To examine this, a transgenic mouse model of Alzheimer's disease (TgCRND8) in vivo were treated intravenously with beta-amyloid antibody-conjugated (Ab), blood-brain barrier-crossing terpolymer (TP) containing polymer-lipid based manganese dioxide nanoparticles (Ab-TP-MDNPs). Alterations in cerebral glucose utilization were determined by [¹⁸F]FDG-PET imaging in vivo, with glucose metabolism and mitochondrial activity analyzed by biomarkers and studies with primary neurons in vitro. Synaptic function was evaluated by both biomarkers and electrophysiologic analysis. Current study shows that intravenously administered Ab-TP-MDNPs enhanced cerebral glucose utilization, improved glucose metabolism, mitochondrial activity, and increased the levels of neprilysin, O-glycosylation. The consequence of this was enhanced glucose and ATP availability, resulting in improved long-term potentiation for promoting neuronal synaptic function. This study highlights the importance of targeting the metabolism of complex disease pathologies in addressing disease-modifying therapeutics for neurodegenerative disorders such as Alzheimer's disease.

논문정보

형식Research article
게재일2025년 01월 (BRIC 등록일 2025-02-07)
연구진국외 연구진
분야 의약학 > 약학

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