Humanin (HN) is an endogenous micropeptide also known as a mitochondria-derived peptide. It has a neuroprotective effect against Alzheimer's disease (AD) and other neurodegenerative diseases by improving hippocampal acetylcholine and attenuating the development of oxidative stress and associated neurotoxicity. HN protects the neuron from the toxic effects of amyloid beta (Aβ). HN is regarded as a biomarker of mitochondrial stress. Interestingly, aging reduces brain expression of HN, leading to cognitive impairment and elevating the risk of neurodegeneration, including AD. However, in old subjects and AD patients, circulating HN levels increase as a compensatory mechanism to reduce neurodegeneration and mitochondrial dysfunction in AD. Conversely, other studies demonstrated a reduction in circulating HN levels in AD. These findings indicated controversial points regarding the precise mechanistic role of HN in AD. Therefore, the aim of this review was to discuss the exact role of HN in AD neuropathology and also to discuss the molecular mechanisms of HN in AD.

Alzheimer's disease (AD), the leading cause of dementia, involves microglial activation, pro-inflammatory cytokine release, and impaired insulin signaling via insulin receptor substrate 1 (IRS-1) inhibition. Brain insulin resistance (BIR) is a key factor in AD progression, disrupting synaptic plasticity and neuronal function. Additionally, glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide (GIP) signaling, which regulate insulin pathways, are compromised in AD. GLP-1/GIP receptor activation or their analogs, such as tirzepatide, show potential in mitigating AD neuropathology. However, the precise neuroprotective mechanisms of tirzepatide remain unclear. This mini-review explores tirzepatide's potential therapeutic effects in AD, focusing on its role in restoring insulin signaling, reducing neuroinflammation, and improving cognitive function. Understanding these mechanisms could offer new insights into AD treatment strategies.