Alsaleem Mansour A, Al-Kuraishy Hayder M, Al-Gareeb Ali I, Abdel-Fattah Maha M, Alrouji Mohammed, Al-Harchan Nasser A, Alruwaili Mubarak, Papadakis Marios, Alexiou Athanasios, Batiha Gaber El-Saber
Unit of Scientific Research, Applied College, Qassim University, Buraydah, Saudi Arabia.
Department of Clinical Pharmacology and Medicine, College of Medicine, Mustansiriyah University, Baghdad, Iraq.
J Cell Mol Med. 2025 Mar;29(5):e70378. doi: 10.1111/jcmm.70378.
Alzheimer's disease (AD) is a neurodegenerative disease caused by the progressive deposition of extracellular amyloid beta (Aβ) and intracellular neurofibrillary tangles (NFTs). Of note, metabolic disorders such as insulin resistance (IR) and type 2 diabetes (T2D) are associated with the development of brain IR and associated neurodegeneration. In addition, AD neuropathology and linked cognitive impairment accelerate the development of peripheral IR and the progression of T2D. Therefore, there is a bidirectional relationship between T2D and AD. It has been demonstrated that AD and T2D induce dysregulation of peroxisome proliferator-activated receptor alpha (PPAR-α) leading to the central and peripheral metabolic disturbances. Hence, dysregulated PPAR-α could be a shared mechanism in both AD and T2D, and restoration of PPAR-α signalling by PPAR-α agonist fenofibrate (FN) may alleviate T2D and AD. Therefore, this review aims to shed light on the potential involvement of PPAR-α in T2D and AD, and how FN could be effective in the management of AD. FN seems to be effective in both AD and T2D by dual neuroprotective and antidiabetic effects that can mitigate AD neuropathology and T2D-related complications by modulating various cellular processes and inflammatory signalling pathways. In conclusion, FN could be a possible candidate in the management of AD and T2D by modulating different signalling pathways involved in the pathogenesis of these conditions.
阿尔茨海默病（AD）是一种由细胞外淀粉样β蛋白（Aβ）和细胞内神经原纤维缠结（NFTs）的渐进性沉积所引起的神经退行性疾病。值得注意的是，诸如胰岛素抵抗（IR）和2型糖尿病（T2D）等代谢紊乱与脑IR的发展及相关神经退行性变有关。此外，AD神经病理学及相关的认知障碍会加速外周IR的发展和T2D的进展。因此，T2D与AD之间存在双向关系。已证实AD和T2D会诱导过氧化物酶体增殖物激活受体α（PPAR-α）失调，导致中枢和外周代谢紊乱。因此，PPAR-α失调可能是AD和T2D的共同机制，通过PPAR-α激动剂非诺贝特（FN）恢复PPAR-α信号传导可能会减轻T2D和AD。因此，本综述旨在阐明PPAR-α在T2D和AD中的潜在作用，以及FN如何有效治疗AD。FN似乎通过双重神经保护和抗糖尿病作用在AD和T2D中均有效，可通过调节各种细胞过程和炎症信号通路减轻AD神经病理学和T2D相关并发症。总之，通过调节这些疾病发病机制中涉及的不同信号通路，FN可能是治疗AD和T2D的一个潜在候选药物。
