Combined administration of buntanetap and dulaglutide counteracts synaptic dysfunction and memory loss in an Alzheimer's disease mouse model

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Abstract

[INTRODUCTION] Alzheimer's disease (AD) results from disruptions in proteostasis, metabolism, and neurotrophic signaling that impair synaptic plasticity and memory. Dulaglutide, a blood-brain barrier (BBB)-permeant glucagon-like peptide-1 (GLP-1) receptor agonist, enhances phosphoinositide 3-kinase (PI3K)/Akt and cAMP response element-binding protein (CREB) signaling, while buntanetap reduces translation of aggregation-prone proteins such as amyloid precursor protein (APP), tau, α-synuclein, and transactive response DNA-binding protein of 43 kDa. Although both compounds show cognitive benefits individually, their potential synergistic effects remain unexplored. [METHODS] APP/presenilin 1 (PS1) mice and wild-type (WT) littermates were treated with dulaglutide or buntanetap at high or subthreshold doses, alone or in combination, beginning at plaque deposition. Spatial memory was assessed through the 2-day radial arm water maze (RAWM), associative memory using contextual fear conditioning, and hippocampal Schaffer collateral-CA1 long-term potentiation (LTP) was evaluated as a measure of synaptic plasticity. Motor, sensory, motivational, and shock-sensitivity controls were included to rule out confounding non-cognitive effects. Meso Scale Discovery and Western blotting analyses were performed on frozen hippocampal tissue to assess amyloid beta (Aβ) and the postsynaptic density protein 95 (PSD95) marker levels. [RESULTS] High doses of either dulaglutide or buntanetap alone rescued deficits in spatial and contextual memory as well as LTP in APP/PS1 mice, whereas lower doses produced minimal or partial benefit. Concurrent administration of low, individually ineffective doses of buntanetap (1 mg/kg) and dulaglutide (0.1 mg/kg) fully rescued RAWM performance, restored contextual fear memory and CA1 LTP, reduced Aβ levels, and restored PSD95. The combination treatment did not alter behavior in WT mice across control behavioral tasks, confirming treatment specificity for AD-related deficits. [DISCUSSION] Our findings demonstrate a strong synergistic interaction between BBB-permeant dulaglutide and buntanetap at subthreshold doses, showing that combined enhancement of neurotrophic signaling and reduction of proteotoxic stress can rescue hippocampal dysfunction in early AD. This convergence between GLP-1 receptor-mediated pathways and inhibition of neurotoxic protein synthesis supports the clinical evaluation of GLP-1-based combination therapies with proteostatic modulators such as buntanetap.

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