Revisiting alzheimer’s disease: the mitochondrial and metabolic nexus shaping neurodegeneration
Abstract
Amyloid-β (Aβ) plaques and neurofibrillary tangles made of hyperphosphorylated tau protein are the two main indicators of Alzheimer's disease (AD), a progressive neurodegenerative illness. There is currently no cure, and symptomatic treatments including newly authorized anti-amyloid immunotherapies only slightly reduce cognitive loss. There is growing evidence that mitochondrial dysfunction appears early in the pathophysiology of AD and may be a primary cause of the disease's development rather than a subsequent one. Neurodegeneration is caused by a variety of mitochondrial abnormalities, including as decreased energy production, aberrant fusion and fission dynamics, elevated reactive oxygen species (ROS), and reduced mitophagy. Furthermore, mitochondrial failure is directly linked to metabolic problems such as brain insulin resistance, dysregulated lipid metabolism, and glucose hypometabolism. According to recent research, dysbiosis of the gut microbiota may exacerbate AD pathogenesis by causing neuroinflammation and metabolic abnormalities via the gut-brain axis. Restoring neuronal energy homeostasis and changing the course of illness may be possible by interventions that target these metabolic and mitochondrial pathways as well as gut bacteria.
Keywords:
Alzheimer’s disease, amyloid-β, neurofibrillary tangles, energy metabolism, reactive oxygen species, neuroinflammation, gut microbiota, metabolic disturbance, neurodegeneration
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19. Chen H, McCaffery JM, Chan DC. Mitochondrial fusion protects against neurodegeneration in the cerebellum. Cell. 2007;130:548–62.
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22. Murphy MP, LeVine III H. Alzheimer's disease and the amyloid-β peptide. J Alzheimers Dis. 2010;19(1):311-23.
23. Swerdlow RH, Burns JM, Khan SM. The Alzheimer's disease mitochondrial cascade hypothesis: progress and perspectives. Biochim Biophys Acta. 2014;1842(8):1219-31.
24. Li Z, Cao Y, Pei H, Ma L, Yang Y, Li H. The contribution of mitochondria-associated endoplasmic reticulum membranes (MAMs) dysfunction in Alzheimer’s disease and the potential countermeasure. Front Neurosci. 2023;17:1158204.
25. Area-Gomez E, de Groof A, Bonilla E, Montesinos J, Tanji K, Boldogh I, Pon L, Schon EA. A key role for MAM in mediating mitochondrial dysfunction in Alzheimer disease. Cell Death Dis. 2018;9(3):335.
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27. Wang Y, Mandelkow E. Tau in physiology and pathology. Nat Rev Neurosci. 2016;17(1):22-35.
28. Avila J, Jiménez JS, Sayas CL, Bolós M, Zabala JC, Rivas G, Hernández F. Tau structures. Front Aging Neurosci. 2016;8:262.
29. Cario A, Berger CL. Tau, microtubule dynamics, and axonal transport: new paradigms for neurodegenerative disease. Bioessays. 2023;45(8):2200138.
30. Olesen MA, Pradenas E, Villavicencio-Tejo F, Porter GA, Johnson GV, Quintanilla RA. Mitochondria-tau association promotes cognitive decline and hippocampal bioenergetic deficits during the aging. Free Radic Biol Med. 2024;217:141-56.
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32. Pérez MJ, Jara C, Quintanilla RA. Contribution of tau pathology to mitochondrial impairment in neurodegeneration. Front Neurosci. 2018;12:441.
33. Vlassenko AG, Gordon BA, Goyal MS, Su Y, Blazey TM, Durbin TJ, Couture LE, Christensen JJ, Jafri H, Morris JC, Raichle ME. Aerobic glycolysis and tau deposition in preclinical Alzheimer's disease. Neurobiol Aging. 2018;67:95-8.
34. Martin SP, Leeman-Markowski BA. Proposed mechanisms of tau: relationships to traumatic brain injury, Alzheimer’s disease, and epilepsy. Front Neurol. 2024;14:1287545.
35. Olesen MA, Pradenas E, Villavicencio-Tejo F, Porter GA, Johnson GV, Quintanilla RA. Mitochondria-tau association promotes cognitive decline and hippocampal bioenergetic deficits during the aging. Free Radic Biol Med. 2024;217:141-56.
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37. Shoshan-Barmatz V, Nahon-Crystal E, Shteinfer-Kuzmine A, Gupta R. VDAC1, mitochondrial dysfunction, and Alzheimer's disease. Pharmacol Res. 2018;131:87-101.
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39. Butterfield DA, Halliwell B. Oxidative stress, dysfunctional glucose metabolism and Alzheimer disease. Nat Rev Neurosci. 2019;20(3):148-60.
40. Jove M, Mota-Martorell N, Torres P, Ayala V, Portero-Otin M, Ferrer I, Pamplona R. The causal role of lipoxidative damage in mitochondrial bioenergetic dysfunction linked to Alzheimer’s disease pathology. Life. 2021;11(5):388.
41. Sweeney MD, Sagare AP, Zlokovic BV. Blood–brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders. Nat Rev Neurol. 2018;14(3):133-51.
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17/12/2025
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Kumari, S., Singh, A. P., & Singh, A. P. (2025). Revisiting alzheimer’s disease: the mitochondrial and metabolic nexus shaping neurodegeneration. The Journal of Multidisciplinary Research, 5(3), 17-26. https://doi.org/10.37022/tjmdr.v5i3.780
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