Chronic ghrelin suppresses amyloid-β production and improves cognition in diabetic rats

Diabetic individuals often exhibit cognitive impairments, a condition linked to the activation of the nuclear factor-kappa B (NF-κB) signaling pathway and subsequent overproduction of amyloid-β (Aβ) protein in the brain. This pathological cascade contributes to neuronal dysfunction and cognitive decline, mirroring aspects of Alzheimer's disease pathology. While ghrelin, a gut-derived hormone, has been previously suggested to have neuroprotective and cognition-enhancing effects, its specific mechanism of action within the diabetic brain's inflammatory and amyloidogenic pathways remained unclear. This study investigates whether ghrelin can directly counteract the diabetes-induced activation of the IKK/NF-κB/BACE1 signaling cascade to mitigate Aβ pathology and restore cognitive function.

Researchers established a diabetic rat model using streptozotocin (STZ) injection. These diabetic rats then received chronic intracerebroventricular (ICV) administration of either ghrelin or its antagonist, (D-lys3)-GHRP-6 (DG). Cognitive function was assessed using the Morris water maze test. Hippocampal tissue was analyzed via Western blot to measure the expression of key proteins, including GHSR-1a, PP1, IKK, NF-κB, BACE1, and Aβ. A parallel in vitro experiment was conducted on primary rat hippocampal neurons treated with high glucose, followed by exposure to ghrelin, DG, a PP1 antagonist, or an IKK antagonist to confirm the signaling pathway.

STZ-induced diabetic rats showed significant cognitive impairment in the Morris water maze test. This cognitive decline was accompanied by a higher expression of amyloid-β (Aβ) and significantly decreased levels of the ghrelin receptor GHSR-1a and protein phosphatase 1 (PP1) in the hippocampus. Concurrently, the study observed increased activation of the pro-inflammatory IKK/NF-κB/BACE1 signaling pathway. Chronic ghrelin administration reversed these effects, improving cognition and suppressing the IKK/NF-κB/BACE1 pathway, which in turn reduced Aβ production.

The therapeutic effects of ghrelin were mediated by protein phosphatase 1 (PP1); ghrelin administration upregulated hippocampal PP1 expression. These benefits were abolished by the co-administration of the ghrelin receptor antagonist (D-lys3)-GHRP-6 (DG). In primary neurons, high glucose mimicked the in vivo findings, and ghrelin's protective effects were reversed by both DG and a PP1 antagonist, while an IKK antagonist enhanced them.