The risk of Alzheimer’s disease (AD) and other forms of cognitive impairment is increased in patients with T2D. Both conditions are characterized by brain insulin resistance and regional brain hypometabolism, and the brain of T2D animal models also exhibit classical AD pathologies (e.g., P-tau, Aβ plaques). Here, we investigated whether pathological changes in brain ECM composition contribute to these shared defects. AD pathology in human hippocampus includes loss of perineuronal nets (PNNs), which are chondroitin sulfate (CS)-containing matrices that regulate key neurocircuit interactions critical to cognitive function. We report that as in humans, rat PNNs (identified by Wisteria floribunda agglutinin (WFA) labeling of CS) are comprised mainly of the CS-proteoglycan aggrecan (ACAN). Furthermore, we report a significant loss of stable WFA+/ACAN+ PNN structures in both the hypothalamus and hippocampus of ZDF rats, an established model of T2D that is also known to develop AD neuropathology, compared to aged-matched WT controls (Hypo: WFA 51.8±8.2% and ACAN 64.9±2.4% decrease; Hippo: WFA 43.9±5.2% and ACAN 25.9±3.8% decrease). PNN matrix stability is strongly influenced by CS composition, with an increase in 6S-CS promoting matrix destabilization. Using a novel mass spectrometry-based approach to characterize the CS composition isolated from brain tissue, we show that the sustained normalization of glycemia by fibroblast growth factor 1 (FGF-1) in T2D-ZDF rats is accompanied by both a reduction in hypothalamic 6S-CS abundance and restoration of normal WFA+/ACAN+ PNN structures (WFA: 2.0±0.2 and ACAN: 2.2±0.2-fold increase). Studies to determine if this is also true in hippocampus are ongoing. These results suggest that destabilized PNN structures cause neurocircuit dysfunction that affects glycemic control and impairs memory. FGF-1-induced normalization of PNNs underscores the potential for neurocircuit remodeling as a therapy for T2DM and AD.


K.M. Alonge: Research Support; Self; Novo Nordisk Inc. M.J. Reed: Stock/Shareholder; Spouse/Partner; Amgen Inc. M.A. Bentsen: None. C. Keene: None. M. Guttman: None. M.W. Schwartz: Consultant; Self; Novo Nordisk A/S. Research Support; Self; Novo Nordisk A/S.


National Institutes of Health; Novo Nordisk

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