The neuroprotective role of Humanin in Alzheimer's disease: The molecular effects

• Published in: European journal of pharmacology Vol. 998; p. 177510
• Main Authors: Alqahtani, Saad Misfer, Al-Kuraishy, Hayder M., Al-Gareeb, Ali I., Alexiou, Athanasios, Fawzy, Mohamed N., Papadakis, Marios, Al-Botaty, Basant M., Alruwaili, Mubarak, El-Saber Batiha, Gaber
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier B.V 05.07.2025
• Subjects: Alzheimer Disease - metabolism; Alzheimer Disease - pathology; Alzheimer's disease; Amyloid beta-Peptides - metabolism; Animals; Brain - metabolism; Brain - pathology; Humanin; Humans; Intracellular Signaling Peptides and Proteins; Mitochondria - metabolism; Mitochondria-derived peptide; Neuropathology; Neuroprotective Agents - metabolism; Neuroprotective Agents - pharmacology; Neuroprotective Agents - therapeutic use; Oxidative Stress; Trimeric receptor; HNG; Oxidative stress; Neuropathology; HN; FPR2; Trimeric receptor; Aβ; PI3K; mTOR; CLSP; JAK2; Alzheimer's disease; AD; CNTFR-α; IGFBP3; Humanin; STAT3; T2D; htHNR; Mitochondria-derived peptide; NFTs; ROS; Bax; ULK1; IL6ST; SHLP
• ISSN: 0014-2999; 1879-0712; 1879-0712
• DOI: 10.1016/j.ejphar.2025.177510

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.