Neuroprotective Mechanisms of Amylin Receptor Activation, Not Antagonism, in the APP/PS1 Mouse Model of Alzheimer’s Disease

Abstract

Background: Amylin, a pancreatic amyloid peptide involved in energy homeostasis, is increasingly studied in the context of Alzheimer’s disease (AD) etiology. To date, conflicting pathogenic and neuroprotective roles for this peptide and its analogs for AD pathogenesis have been described. Objective: Whether the benefits of amylin are associated with peripheral improvement of metabolic tone/function or directly through the activation of central amylin receptors is also unknown and downstream signaling mechanisms of amylin receptors are major objectives of this study. Methods: To address these questions more directly we delivered the amylin analog pramlintide systemically (IP), at previously identified therapeutic doses, while centrally (ICV) inhibiting the receptor using an amylin receptor antagonist (AC187), at doses known to impact CNS function. Results: Here we show that pramlintide improved cognitive function independently of CNS receptor activation and provide transcriptomic data that highlights potential mechanisms. Furthermore, we show than inhibition of the amylin receptor increased amyloid-beta pathology in female APP/PS1 mice, an effect than was mitigated by peripheral delivery of pramlintide. Through transcriptomic analysis of pramlintide therapy in AD-modeled mice we found sexual dimorphic modulation of neuroprotective mechanisms: oxidative stress protection in females and membrane stability and reduced neuronal excitability markers in males. Conclusion: These data suggest an uncoupling of functional and pathology-related events and highlighting a more complex receptor system and pharmacological relationship that must be carefully studied to clarify the role of amylin in CNS function and AD.

The LH receptor regulates hippocampal spatial memory and restores dendritic spine density in ovariectomized APP/PS1 AD mice

“…Starting at the beginning of the hippocampus, [−.94mm from Bregma], every 6 th slice was stained using 1% ThioflavinS. Sections were taken through a series of 5-minute incubation steps at room temperature, as described in (Corrigan et al, 2023). Sections were then mounted on slides, allowed to dry, then taken through EtOH and Xylene dehydration and clearing steps and coverslipped using permount mounting medium (Electron Microscopy Science, PA).…”

“…Starting at the beginning of the hippocampus, [-.94mm from Bregma], every 6 th slice was stained using 1% ThioflavinS. Sections were taken through a series of 5-minute incubation steps at room temperature, as described in (Corrigan et al, 2023).…”

GLP-1 Analogs, SGLT-2, and DPP-4 Inhibitors: A Triad of Hope for Alzheimer’s Disease Therapy

“…These amyloid deposits contribute to pancreatic beta cell dysfunction and decreased insulin secretion, characteristic features of T2D. Such a correlation may lead to disruptions in the regulation of glucose metabolism, creating a favorable ground for the evolution of processes related to neurodegenerative diseases [71]. Interestingly, similar amyloid deposits composed of amylin have been identified in the brains of individuals with T2D and Alzheimer's disease [72][73][74].…”