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image of β-Amyloid Pathways in Alzheimer's Disease: Mechanisms and Therapeutic Targets

Abstract

Alzheimer's disease (AD) is a typical neurodegenerative illness, and it is a main cause of dementia, affecting millions of older populations throughout the world. Although the exact causes of AD are still not clear, the disorder is known to be considered by the accumulation of amyloid plaques and tau tangles in the neuronal cells. Currently, available drugs such as cholinesterase inhibitors and NMDA antagonists can help manage symptoms but don’t address the underlying causes of the disease. New experimental treatments targeting amyloid and tau proteins show promise but are still in clinical trials. Recently, β-Amyloid has gained attention as an emerging target to develop new medications as it is strongly involved in the pathophysiology of AD. β-Amyloidpathies are directly or indirectly linked with multiple pathways, including GSK3β, insulin resistance, NMDA dysfunction, AMP-activated kinase, cholesterol mechanism, mitochondrial dysfunction, neuroinflammation, and SIRT1. However, several β-Amyloid targeting therapies employing various mechanisms have shown partial success in clinical trials, possibly due to a lack of understanding of the molecular link of this peptide with other pathways. Therefore, this paper has discussed the β-Amyloid molecular mechanisms involved in pathophysiological pathways to manage neuronal disorders and intracellular signal transduction effectively.

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2025-06-27
2025-09-19

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References

  1. Koenig A.M. Nobuhara C.K. Williams V.J. Arnold S.E. Biomarkers in Alzheimer’s, frontotemporal, Lewy body, and vascular dementias. Focus Am. Psychiatr. Publ. 2018 16 2 164 172 10.1176/appi.focus.20170048 31975911
    [Google Scholar]
  2. Sharma K. Cholinesterase inhibitors as Alzheimer’s therapeutics.(Review) Mol. Med. Rep. 2019 20 2 1479 1487 10.3892/mmr.2019.10374 31257471
    [Google Scholar]
  3. Hippius H. Neundörfer G. The discovery of Alzheimer’s disease. Dialogues Clin. Neurosci. 2003 5 1 101 108 10.31887/DCNS.2003.5.1/hhippius 22034141
    [Google Scholar]
  4. Bondi M.W. Edmonds E.C. Salmon D.P. Alzheimer’s disease: Past, present, and future. J. Int. Neuropsychol. Soc. 2017 23 9-10 818 831 10.1017/S135561771700100X 29198280
    [Google Scholar]
  5. Marucci G. Buccioni M. Ben D.D. Lambertucci C. Volpini R. Amenta F. Efficacy of acetylcholinesterase inhibitors in Alzheimer’s disease. Neuropharmacology 2021 190 108352 10.1016/j.neuropharm.2020.108352 33035532
    [Google Scholar]
  6. Chow V.W. Mattson M.P. Wong P.C. Gleichmann M. An overview of APP processing enzymes and products. Neuromolecular Med. 2010 12 1 1 12 10.1007/s12017‑009‑8104‑z 20232515
    [Google Scholar]
  7. Tu S. Okamoto S. Lipton S.A. Xu H. Oligomeric Aβ-induced synaptic dysfunction in Alzheimer’s disease. Mol. Neurodegener. 2014 9 1 48 10.1186/1750‑1326‑9‑48 25394486
    [Google Scholar]
  8. Tomita T. Molecular mechanism of intramembrane proteolysis by γ-secretase. J. Biochem. 2014 156 4 195 201 10.1093/jb/mvu049 25108625
    [Google Scholar]
  9. Selkoe D.J. Cell biology of protein misfolding: The examples of Alzheimer’s and Parkinson’s diseases. Nat. Cell Biol. 2004 6 11 1054 1061 10.1038/ncb1104‑1054 15516999
    [Google Scholar]
  10. Lobine D. Sadeer N. Jugreet S. Potential of medicinal plants as neuroprotective and therapeutic properties against amyloid-β-related toxicity, and glutamate-induced excitotoxicity in human neural cells. Curr. Neuropharmacol. 2021 19 9 1416 1441 10.2174/1570159X19666210412095251 33845746
    [Google Scholar]
  11. Mahoney-Sanchez L. Belaidi A.A. Bush A.I. Ayton S. The complex role of apolipoprotein E in Alzheimer’s disease: An overview and update. J. Mol. Neurosci. 2016 60 3 325 335 10.1007/s12031‑016‑0839‑z 27647307
    [Google Scholar]
  12. Kaur D. Sharma V. Deshmukh R. Activation of microglia and astrocytes: A roadway to neuroinflammation and Alzheimer’s disease. Inflammopharmacology 2019 27 4 663 677 10.1007/s10787‑019‑00580‑x 30874945
    [Google Scholar]
  13. Avila J. Tau phosphorylation and aggregation in Alzheimer’s disease pathology. FEBS Lett. 2006 580 12 2922 2927 10.1016/j.febslet.2006.02.067 16529745
    [Google Scholar]
  14. Jeong H. Shin H. Hong S. Kim Y. Physiological roles of monomeric amyloid-β and implications for Alzheimer’s disease therapeutics. Exp. Neurobiol. 2022 31 2 65 88 10.5607/en22004 35673997
    [Google Scholar]
  15. Hampel H. Amyloid-β and cognition in aging and Alzheimer’s disease: Molecular and neurophysiological mechanisms. J. Alzheimers Dis. 2012 33 s1 S79 S86 10.3233/JAD‑2012‑129003 22531423
    [Google Scholar]
  16. Danysz W. Parsons C.G. Alzheimer’s disease, β‐amyloid, glutamate, NMDA receptors and memantine – searching for the connections. Br. J. Pharmacol. 2012 167 2 324 352 10.1111/j.1476‑5381.2012.02057.x 22646481
    [Google Scholar]
  17. Vieira M. Yong X.L.H. Roche K.W. Anggono V. Regulation of NMDA glutamate receptor functions by the GluN2 subunits. J. Neurochem. 2020 154 2 121 143 10.1111/jnc.14970 31978252
    [Google Scholar]
  18. Swanger S.A. Vance K.M. Acker T.M. A novel negative allosteric modulator selective for GluN2C/2D-containing NMDA receptors inhibits synaptic transmission in hippocampal interneurons. ACS Chem. Neurosci. 2018 9 2 306 319 10.1021/acschemneuro.7b00329 29043770
    [Google Scholar]
  19. Benke T. Traynelis S.F. AMPA-type glutamate receptor conductance changes and plasticity: Still a lot of noise. Neurochem. Res. 2019 44 3 539 548 10.1007/s11064‑018‑2491‑1 29476449
    [Google Scholar]
  20. Lei P. Ayton S. Bush A.I. The essential nlms of Alzheimer’s disease. J. Biol. Chem. 2021 296 100105 10.1074/jbc.REV120.008207 33219130
    [Google Scholar]
  21. Ittner L.M. Ke Y.D. Delerue F. Dendritic function of tau mediates amyloid-β toxicity in Alzheimer’s disease mouse models. Cell 2010 142 3 387 397 10.1016/j.cell.2010.06.036 20655099
    [Google Scholar]
  22. Moreau A.W. Kullmann D.M. NMDA receptor-dependent function and plasticity in inhibitory circuits. Neuropharmacology 2013 74 23 31 10.1016/j.neuropharm.2013.03.004 23537500
    [Google Scholar]
  23. Wang R. Reddy P.H. Role of glutamate and NMDA receptors in Alzheimer’s disease. J. Alzheimers Dis. 2017 57 4 1041 1048 10.3233/JAD‑160763 27662322
    [Google Scholar]
  24. Chen G. Xu T. Yan Y. Amyloid beta: Structure, biology and structure-based therapeutic development. Acta Pharmacol. Sin. 2017 38 9 1205 1235 10.1038/aps.2017.28 28713158
    [Google Scholar]
  25. Khan T. Waseem R. Zehra Z. Mitochondrial dysfunction: Pathophysiology and mitochondria-targeted drug delivery approaches. Pharmaceutics 2022 14 12 2657 10.3390/pharmaceutics14122657 36559149
    [Google Scholar]
  26. Mota S.I. Ferreira I.L. Pereira C. Oliveira C.R. Rego A.C. Amyloid-beta peptide 1-42 causes microtubule deregulation through N-methyl-D-aspartate receptors in mature hippocampal cultures. Curr. Alzheimer Res. 2012 9 7 844 856 10.2174/156720512802455322 22631440
    [Google Scholar]
  27. Muzio L. Viotti A. Martino G. Microglia in neuroinflammation and neurodegeneration: From understanding to therapy. Front. Neurosci. 2021 15 742065 10.3389/fnins.2021.742065 34630027
    [Google Scholar]
  28. Italia M. Ferrari E. Diluca M. Gardoni F. NMDA And AMPA receptors at synapses: Novel targets for tau and α-synuclein proteinopathies. Biomedicines 2022 10 7 1550 10.3390/biomedicines10071550 35884851
    [Google Scholar]
  29. Hooper C. Markevich V. Plattner F. Glycogen synthase kinase-3 inhibition is integral to long-term potentiation. Eur. J. Neurosci. 2007 25 1 81 86 10.1111/j.1460‑9568.2006.05245.x 17241269
    [Google Scholar]
  30. Ly P.T.T. Wu Y. Zou H. Inhibition of GSK3β-mediated BACE1 expression reduces Alzheimer-associated phenotypes. J. Clin. Invest. 2013 123 1 224 235 10.1172/JCI64516 23202730
    [Google Scholar]
  31. Zhang W. Yang J. Liu Y. PR55 α, a regulatory subunit of PP2A, specifically regulates PP2A-mediated β-catenin dephosphorylation. J. Biol. Chem. 2009 284 34 22649 22656 10.1074/jbc.M109.013698 19556239
    [Google Scholar]
  32. Dahiya M. Yadav M. Goyal C. Kumar A. Insulin resistance in Alzheimer’s disease: Signalling mechanisms and therapeutics strategies. Inflammopharmacology 2025 33 4 1817 1831 10.1007/s10787‑025‑01704‑2 40064805
    [Google Scholar]
  33. Uemura K. Kuzuya A. Shimozono Y. GSK3β activity modifies the localization and function of presenilin 1. J. Biol. Chem. 2007 282 21 15823 15832 10.1074/jbc.M610708200 17389597
    [Google Scholar]
  34. Cole S.L. Vassar R. The Alzheimer’s disease β-secretase enzyme, BACE1. Mol. Neurodegener. 2007 2 1 22 10.1186/1750‑1326‑2‑22 18005427
    [Google Scholar]
  35. Chen C.H. Zhou W. Liu S. Increased NF-κB signalling up-regulates BACE1 expression and its therapeutic potential in Alzheimer’s disease. Int. J. Neuropsychopharmacol. 2012 15 1 77 90 10.1017/S1461145711000149 21329555
    [Google Scholar]
  36. Medeiros R. Baglietto-Vargas D. LaFerla F.M. The role of tau in Alzheimer’s disease and related disorders. CNS Neurosci. Ther. 2011 17 5 514 524 10.1111/j.1755‑5949.2010.00177.x 20553310
    [Google Scholar]
  37. Bustos V. Pulina M.V. Ledo J. Amyloidogenic and anti-amyloidogenic properties of presenilin 1. Adv. Pharmacol. 2021 90 239 251 10.1016/bs.apha.2020.09.010 33706935
    [Google Scholar]
  38. Won J.S. Im Y.B. Kim J. Singh A.K. Singh I. Involvement of AMP-activated-protein-kinase (AMPK) in neuronal amyloidogenesis. Biochem. Biophys. Res. Commun. 2010 399 4 487 491 10.1016/j.bbrc.2010.07.081 20659426
    [Google Scholar]
  39. Chen Y. Zhou K. Wang R. Antidiabetic drug metformin (Glucophage R) increases biogenesis of Alzheimer’s amyloid peptides via up-regulating BACE1 transcription. Proc. Natl. Acad. Sci. USA 2009 106 10 3907 3912 10.1073/pnas.0807991106 19237574
    [Google Scholar]
  40. Liu F. Li B. Tung E.J. Grundke-Iqbal I. Iqbal K. Gong C.X. Site-specific effects of tau phosphorylation on its microtubule assembly activity and self-aggregation. Eur. J. Neurosci. 2007 26 12 3429 3436 10.1111/j.1460‑9568.2007.05955.x 18052981
    [Google Scholar]
  41. Manning B.D. Toker A. AKT/PKB signaling: Navigating the network. Cell 2017 169 3 381 405 10.1016/j.cell.2017.04.001 28431241
    [Google Scholar]
  42. Mîinea C.P. Sano H. Kane S. AS160, the Akt substrate regulating GLUT4 translocation, has a functional Rab GTPase-activating protein domain. Biochem. J. 2005 391 1 87 93 10.1042/BJ20050887 15971998
    [Google Scholar]
  43. Huang X. Liu G. Guo J. Su Z. The PI3K/AKT pathway in obesity and type 2 diabetes. Int. J. Biol. Sci. 2018 14 11 1483 1496 10.7150/ijbs.27173 30263000
    [Google Scholar]
  44. Gaugel J. Haacke N. Sehgal R. Picalm, a novel regulator of GLUT4-trafficking in adipose tissue. Mol. Metab. 2024 88 102014 10.1016/j.molmet.2024.102014 39182843
    [Google Scholar]
  45. Watson R.T. Pessin J.E. Intracellular organization of insulin signaling and GLUT4 translocation. Recent Prog. Horm. Res. 2001 56 1 175 194 10.1210/rp.56.1.175 11237212
    [Google Scholar]
  46. Ma X. Zhang J. Burgess P. Rossi S. Huang B. Interactive effects of melatonin and cytokinin on alleviating drought-induced leaf senescence in creeping bentgrass (Agrostis stolonifera). Environ. Exp. Bot. 2018 145 1 11 10.1016/j.envexpbot.2017.10.010
    [Google Scholar]
  47. Manikandan A. T S S, Manoj N, Vemparala S, Dixit M. In-silico identification of Tyr232 in AMPKα2 as a dephosphorylation site for the protein tyrosine phosphatase PTP-PEST. Proteins 2023 91 6 831 846 10.1002/prot.26470 36645312
    [Google Scholar]
  48. Jäger S. Handschin C. St-Pierre J. Spiegelman B.M. AMP-activated protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1α. Proc. Natl. Acad. Sci. USA 2007 104 29 12017 12022 10.1073/pnas.0705070104 17609368
    [Google Scholar]
  49. Di Lorenzo D. Tau protein and tauopathies: Exploring tau protein-protein and microtubule interactions, cross-interactions and therapeutic strategies. ChemMedChem 2024 19 21 e202400180 10.1002/cmdc.202400180 39031682
    [Google Scholar]
  50. Guo T. Noble W. Hanger D.P. Roles of tau protein in health and disease. Acta Neuropathol. 2017 133 5 665 704 10.1007/s00401‑017‑1707‑9 28386764
    [Google Scholar]
  51. Panda D. Samuel J.C. Massie M. Feinstein S.C. Wilson L. Differential regulation of microtubule dynamics by three- and four-repeat tau: Implications for the onset of neurodegenerative disease. Proc. Natl. Acad. Sci. USA 2003 100 16 9548 9553 10.1073/pnas.1633508100 12886013
    [Google Scholar]
  52. Buchholz S. Zempel H. The six brain-specific TAU isoforms and their role in Alzheimer’s disease and related neurodegenerative dementia syndromes. Alzheimers Dement. 2024 20 5 3606 3628 10.1002/alz.13784 38556838
    [Google Scholar]
  53. Höglinger G.U. Respondek G. Kovacs G.G. New classification of tauopathies. Rev. Neurol. (Paris) 2018 174 9 664 668 10.1016/j.neurol.2018.07.001 30098799
    [Google Scholar]
  54. Zhang Y. Wu K.M. Yang L. Dong Q. Yu J.T. Tauopathies: New perspectives and challenges. Mol. Neurodegener. 2022 17 1 28 10.1186/s13024‑022‑00533‑z 35392986
    [Google Scholar]
  55. Stefanoska K. Gajwani M. Tan A.R.P. Alzheimer’s disease: Ablating single master site abolishes tau hyperphosphorylation. Sci. Adv. 2022 8 27 eabl8809 10.1126/sciadv.abl8809 35857446
    [Google Scholar]
  56. Lee V.M.Y. Goedert M. Trojanowski J.Q. Neurodegenerative Tauopathies. Annu. Rev. Neurosci. 2001 24 1 1121 1159 10.1146/annurev.neuro.24.1.1121 11520930
    [Google Scholar]
  57. Clavaguera F. Bolmont T. Crowther R.A. Transmission and spreading of tauopathy in transgenic mouse brain. Nat. Cell Biol. 2009 11 7 909 913 10.1038/ncb1901 19503072
    [Google Scholar]
  58. Alonso A.D. Beharry C. Corbo C.P. Cohen L.S. Molecular mechanism of prion-like tau-induced neurodegeneration. Alzheimers Dement. 2016 12 10 1090 1097 10.1016/j.jalz.2015.12.014 27126544
    [Google Scholar]
  59. Bloom G.S. Amyloid-β and Tau. JAMA Neurol. 2014 71 4 505 508 10.1001/jamaneurol.2013.5847 24493463
    [Google Scholar]
  60. Wang Y. Mandelkow E. Tau in physiology and pathology. Nat. Rev. Neurosci. 2016 17 1 22 35 10.1038/nrn.2015.1 26631930
    [Google Scholar]
  61. Luo J. Yang H. Song B.L. Mechanisms and regulation of cholesterol homeostasis. Nat. Rev. Mol. Cell Biol. 2020 21 4 225 245 10.1038/s41580‑019‑0190‑7 31848472
    [Google Scholar]
  62. Pfrieger F.W. Ungerer N. Cholesterol metabolism in neurons and astrocytes. Prog. Lipid Res. 2011 50 4 357 371 10.1016/j.plipres.2011.06.002 21741992
    [Google Scholar]
  63. Zhang H. Wei W. Zhao M. Interaction between Aβ and tau in the pathogenesis of Alzheimer’s disease. Int. J. Biol. Sci. 2021 17 9 2181 2192 10.7150/ijbs.57078 34239348
    [Google Scholar]
  64. Duyckaerts C. Braak H. Brion J.P. PART is part of Alzheimer disease. Acta Neuropathol. 2015 129 5 749 756 10.1007/s00401‑015‑1390‑7 25628035
    [Google Scholar]
  65. Musiek E.S. Holtzman D.M. Three dimensions of the amyloid hypothesis: Time, space and ‘wingmen’. Nat. Neurosci. 2015 18 6 800 806 10.1038/nn.4018 26007213
    [Google Scholar]
  66. Gulisano W. Maugeri D. Baltrons M.A. Role of amyloid-β and tau proteins in Alzheimer’s disease: Confuting the amyloid cascade. J. Alzheimers Dis. 2018 64 s1 S611 S631 10.3233/JAD‑179935 29865055
    [Google Scholar]
  67. Lonze B.E. Ginty D.D. Function and regulation of CREB family transcription factors in the nervous system. Neuron 2002 35 4 605 623 10.1016/S0896‑6273(02)00828‑0 12194863
    [Google Scholar]
  68. Carlezon W. Duman R. Nestler E. The many faces of CREB. Trends Neurosci. 2005 28 8 436 445 10.1016/j.tins.2005.06.005 15982754
    [Google Scholar]
  69. Walsh D.M. Selkoe D.J. Aβ Oligomers: A decade of discovery. J. Neurochem. 2007 101 5 1172 1184 10.1111/j.1471‑4159.2006.04426.x 17286590
    [Google Scholar]
  70. Guerrero-Muñoz M.J. Gerson J. Castillo-Carranza D.L. Tau oligomers: The toxic player at synapses in Alzheimer’s disease. Front. Cell. Neurosci. 2015 9 464 10.3389/fncel.2015.00464 26696824
    [Google Scholar]
  71. Song J.H. Yu J.T. Tan L. Brain-derived neurotrophic factor in Alzheimer’s disease: Risk, mechanisms, and therapy. Mol. Neurobiol. 2015 52 3 1477 1493 10.1007/s12035‑014‑8958‑4 25354497
    [Google Scholar]
  72. Li X. Zhang J. Li D. Astrocytic ApoE reprograms neuronal cholesterol metabolism and histone-acetylation-mediated memory. Neuron 2021 109 6 957 970.e8 10.1016/j.neuron.2021.01.005 33503410
    [Google Scholar]
  73. Fabelo N. Martín V. Marín R. Moreno D. Ferrer I. Díaz M. Altered lipid composition in cortical lipid rafts occurs at early stages of sporadic Alzheimer’s disease and facilitates APP/BACE1 interactions. Neurobiol. Aging 2014 35 8 1801 1812 10.1016/j.neurobiolaging.2014.02.005 24613671
    [Google Scholar]
  74. Loving B.A. Bruce K.D. Lipid and lipoprotein metabolism in microglia. Front. Physiol. 2020 11 393 10.3389/fphys.2020.00393 32411016
    [Google Scholar]
  75. McQuade A. Blurton-Jones M. Microglia in Alzheimer’s disease: Exploring how genetics and phenotype influence risk. J. Mol. Biol. 2019 431 9 1805 1817 10.1016/j.jmb.2019.01.045 30738892
    [Google Scholar]
  76. Gamba P. Testa G. Gargiulo S. Staurenghi E. Poli G. Leonarduzzi G. Oxidized cholesterol as the driving force behind the development of Alzheimer’s disease. Front. Aging Neurosci. 2015 7 119 10.3389/fnagi.2015.00119 26150787
    [Google Scholar]
  77. Liu Q. An Y. Yu H. Relationship between oxysterols and mild cognitive impairment in the elderly: A case–control study. Lipids Health Dis. 2016 15 1 177 10.1186/s12944‑016‑0344‑y 27724967
    [Google Scholar]
  78. Testa G. Staurenghi E. Zerbinati C. Changes in brain oxysterols at different stages of Alzheimer’s disease: Their involvement in neuroinflammation. Redox Biol. 2016 10 24 33 10.1016/j.redox.2016.09.001 27687218
    [Google Scholar]
  79. Ricciarelli R. Canepa E. Marengo B. Cholesterol and Alzheimer’s disease: A still poorly understood correlation. IUBMB Life 2012 64 12 931 935 10.1002/iub.1091 23124820
    [Google Scholar]
  80. Hannaoui S. Shim S. Cheng Y. Corda E. Gilch S. Cholesterol balance in prion diseases and Alzheimer’s disease. Viruses 2014 6 11 4505 4535 10.3390/v6114505 25419621
    [Google Scholar]
  81. Akyol O. Akyol S. Chou M.C. Lipids and lipoproteins may play a role in the neuropathology of Alzheimer’s disease. Front. Neurosci. 2023 17 1275932 10.3389/fnins.2023.1275932 38033552
    [Google Scholar]
  82. Thapa R. Moglad E. Afzal M. The role of sirtuin 1 in ageing and neurodegenerative disease: A molecular perspective. Ageing Res. Rev. 2024 102 102545 10.1016/j.arr.2024.102545 39423873
    [Google Scholar]
  83. Zhang X.L. Zhao N. Xu B. Chen X.H. Li T.J. Treadmill exercise inhibits amyloid-β generation in the hippocampus of APP/PS1 transgenic mice by reducing cholesterol-mediated lipid raft formation. Neuroreport 2019 30 7 498 503 10.1097/WNR.0000000000001230 30882716
    [Google Scholar]
  84. Koo J.H. Kang E.B. Oh Y.S. Yang D.S. Cho J.Y. Treadmill exercise decreases amyloid-β burden possibly via activation of SIRT-1 signaling in a mouse model of Alzheimer’s disease. Exp. Neurol. 2017 288 142 152 10.1016/j.expneurol.2016.11.014 27889467
    [Google Scholar]
  85. Qin W. Yang T. Ho L. Neuronal SIRT1 activation as a novel mechanism underlying the prevention of Alzheimer disease amyloid neuropathology by calorie restriction. J. Biol. Chem. 2006 281 31 21745 21754 10.1074/jbc.M602909200 16751189
    [Google Scholar]
  86. Zhang Z. Shen Q. Wu X. Zhang D. Xing D. Activation of PKA/SIRT1 signaling pathway by photobiomodulation therapy reduces Aβ levels in Alzheimer’s disease models. Aging Cell 2020 19 1 e13054 10.1111/acel.13054 31663252
    [Google Scholar]
  87. McKenzie J.A. Spielman L.J. Pointer C.B. Neuroinflammation as a common mechanism associated with the modifiable risk factors for Alzheimer’s and Parkinson’s diseases. Curr. Aging Sci. 2017 10 3 158 176 10.2174/1874609810666170315113244 28302047
    [Google Scholar]
  88. Gerhart-Hines Z. Dominy J.E. Blättler S.M. The cAMP/PKA pathway rapidly activates SIRT1 to promote fatty acid oxidation independently of changes in NAD. Mol. Cell 2011 44 6 851 863 10.1016/j.molcel.2011.12.005 22195961
    [Google Scholar]
  89. Wang R. Li J.J. Diao S. Metabolic stress modulates Alzheimer’s β-secretase gene transcription via SIRT1-PPARγ-PGC-1 in neurons. Cell Metab. 2013 17 5 685 694 10.1016/j.cmet.2013.03.016 23663737
    [Google Scholar]
  90. Chen J. Zhou Y. Mueller-Steiner S. SIRT1 protects against microglia-dependent amyloid-β toxicity through inhibiting NF-kappaB signaling. J. Biol. Chem. 2005 280 48 40364 40374 10.1074/jbc.M509329200 16183991
    [Google Scholar]
  91. Dahiya M. Kumar A. Yadav M. Chauhan S. β-pinene ameliorates ICV-STZ induced Alzheimer’s pathology via antioxidant, anticholinesterase, and mitochondrial protective effects: In-silico and in-vivo studies. Eur. J. Pharmacol. 2025 991 177307 10.1016/j.ejphar.2025.177307 39870228
    [Google Scholar]
  92. Kühlbrandt W. Structure and function of mitochondrial membrane protein complexes. BMC Biol. 2015 13 1 89 10.1186/s12915‑015‑0201‑x 26515107
    [Google Scholar]
  93. Bhatti J.S. Bhatti G.K. Reddy P.H. Mitochondrial dysfunction and oxidative stress in metabolic disorders: A step towards mitochondria based therapeutic strategies. Biochim. Biophys. Acta Mol. Basis Dis. 2017 1863 5 1066 1077 10.1016/j.bbadis.2016.11.010 27836629
    [Google Scholar]
  94. Di Meo S. Reed T.T. Venditti P. Victor V.M. Role of ROS and RNS sources in physiological and pathological conditions. Oxid. Med. Cell. Longev. 2016 2016 1 1245049 10.1155/2016/1245049 27478531
    [Google Scholar]
  95. Han K. Jin X. Guo X. Nrf2 knockout altered brain iron deposition and mitigated age-related motor dysfunction in aging mice. Free Radic. Biol. Med. 2021 162 592 602 10.1016/j.freeradbiomed.2020.11.019 33248265
    [Google Scholar]
  96. Barber R.C. The genetics of Alzheimer’s disease. Scientifica (Cairo) 2012 2012 1 1 14 10.6064/2012/246210 24278680
    [Google Scholar]
  97. Berchtold M.W. Brinkmeier H. Müntener M. Calcium ion in skeletal muscle: Its crucial role for muscle function, plasticity, and disease. Physiol. Rev. 2000 80 3 1215 1265 10.1152/physrev.2000.80.3.1215 10893434
    [Google Scholar]
  98. Halliwell B. Oxidative stress and neurodegeneration: Where are we now? J. Neurochem. 2006 97 6 1634 1658 10.1111/j.1471‑4159.2006.03907.x 16805774
    [Google Scholar]
  99. Jomova K. Raptova R. Alomar S.Y. Reactive oxygen species, toxicity, oxidative stress, and antioxidants: Chronic diseases and aging. Arch. Toxicol. 2023 97 10 2499 2574 10.1007/s00204‑023‑03562‑9 37597078
    [Google Scholar]
  100. Bonen A. PGC-1α-induced improvements in skeletal muscle metabolism and insulin sensitivity. Appl. Physiol. Nutr. Metab. 2009 34 3 307 314 10.1139/H09‑008 19448691
    [Google Scholar]
  101. Grewal R. Reutzel M. Dilberger B. Purified oleocanthal and ligstroside protect against mitochondrial dysfunction in models of early Alzheimer’s disease and brain ageing. Exp. Neurol. 2020 328 113248 10.1016/j.expneurol.2020.113248 32084452
    [Google Scholar]
  102. Quirós P.M. Mottis A. Auwerx J. Mitonuclear communication in homeostasis and stress. Nat. Rev. Mol. Cell Biol. 2016 17 4 213 226 10.1038/nrm.2016.23 26956194
    [Google Scholar]
  103. Kim J. Kundu M. Viollet B. Guan K.L. AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat. Cell Biol. 2011 13 2 132 141 10.1038/ncb2152 21258367
    [Google Scholar]
  104. Kou X. Li J. Liu X. Yang X. Fan J. Chen N. Ampelopsin attenuates the atrophy of skeletal muscle from d-gal-induced aging rats through activating AMPK/SIRT1/PGC-1α signaling cascade. Biomed. Pharmacother. 2017 90 311 320 10.1016/j.biopha.2017.03.070 28364603
    [Google Scholar]
  105. Selvatici R. Marani L. Marino S. Siniscalchi A. In vitro mitochondrial failure and oxidative stress mimic biochemical features of Alzheimer disease. Neurochem. Int. 2013 63 2 112 120 10.1016/j.neuint.2013.05.005 23722080
    [Google Scholar]
  106. Ji R. Jia F. Chen X. Wang Z. Jin W. Yang J. Salidroside alleviates oxidative stress and apoptosis via AMPK/Nrf2 pathway in DHT-induced human granulosa cell line KGN. Arch. Biochem. Biophys. 2022 715 109094 10.1016/j.abb.2021.109094 34813774
    [Google Scholar]
  107. Chen Y. Qing W. Sun M. Lv L. Guo D. Jiang Y. Melatonin protects hepatocytes against bile acid-induced mitochondrial oxidative stress via the AMPK-SIRT3-SOD2 pathway. Free Radic. Res. 2015 49 10 1275 1284 10.3109/10715762.2015.1067806 26118716
    [Google Scholar]
  108. Zhang Z. Yang X. Song Y.Q. Tu J. Autophagy in Alzheimer’s disease pathogenesis: Therapeutic potential and future perspectives. Ageing Res. Rev. 2021 72 101464 10.1016/j.arr.2021.101464 34551326
    [Google Scholar]
  109. Rapaka D. Bitra V.R. Challa S.R. Adiukwu P.C. mTOR signaling as a molecular target for the alleviation of Alzheimer’s disease pathogenesis. Neurochem. Int. 2022 155 105311 10.1016/j.neuint.2022.105311 35218870
    [Google Scholar]
  110. Vingtdeux V. Giliberto L. Zhao H. AMP-activated protein kinase signaling activation by resveratrol modulates amyloid-β peptide metabolism. J. Biol. Chem. 2010 285 12 9100 9113 10.1074/jbc.M109.060061 20080969
    [Google Scholar]
  111. Preman P. Alfonso-Triguero M. Alberdi E. Verkhratsky A. Arranz A.M. Astrocytes in Alzheimer’s disease: Pathological significance and molecular pathways. Cells 2021 10 3 540 10.3390/cells10030540 33806259
    [Google Scholar]
  112. Arafa S.S. El-Di S.B. Hewedy O.A. Flubendiamide provokes oxidative stress, inflammation, miRNAs alteration, and cell cycle deregulation in human prostate epithelial cells: The attenuation impact of synthesized nano-selenium using Trichodermaaureoviride. Chemosphere 2014 265 143305 10.2174/1871527313666140806144831
    [Google Scholar]
  113. Jay T.R. Miller C.M. Cheng P.J. TREM2 deficiency eliminates TREM2+ inflammatory macrophages and ameliorates pathology in Alzheimer’s disease mouse models. J. Exp. Med. 2015 212 3 287 295 10.1084/jem.20142322 25732305
    [Google Scholar]
  114. Baik S.H. Kang S. Son S.M. Mook-Jung I. Microglia contributes to plaque growth by cell death due to uptake of amyloid β in the brain of Alzheimer’s disease mouse model. Glia 2016 64 12 2274 2290 10.1002/glia.23074 27658617
    [Google Scholar]
  115. Santos G. Barateiro A. Gomes C.M. Brites D. Fernandes A. Impaired oligodendrogenesis and myelination by elevated S100B levels during neurodevelopment. Neuropharmacology 2018 129 69 83 10.1016/j.neuropharm.2017.11.002 29126910
    [Google Scholar]
  116. Buffo A. Rolando C. Ceruti S. Astrocytes in the damaged brain: Molecular and cellular insights into their reactive response and healing potential. Biochem. Pharmacol. 2010 79 2 77 89 10.1016/j.bcp.2009.09.014 19765548
    [Google Scholar]
  117. Xie P. TRAF molecules in cell signaling and in human diseases. J. Mol. Signal. 2013 8 1 7 10.1186/1750‑2187‑8‑7 23758787
    [Google Scholar]
  118. Ferrero E. Zocchi M.R. Magni E. Roles of tumor necrosis factor p55 and p75 receptors in TNF-α-induced vascular permeability. Am. J. Physiol. Cell Physiol. 2001 281 4 C1173 C1179 10.1152/ajpcell.2001.281.4.C1173 11546653
    [Google Scholar]
  119. Vandenbark A.A. Offner H. Matejuk S. Matejuk A. Microglia and astrocyte involvement in neurodegeneration and brain cancer. J. Neuroinflammation 2021 18 1 298 10.1186/s12974‑021‑02355‑0 34949203
    [Google Scholar]
  120. Foley K.E. Winder Z. Sudduth T.L. Alzheimer’s disease and inflammatory biomarkers positively correlate in plasma in the UK-ADRC cohort. Alzheimers Dement. 2024 20 2 1374 1386 10.1002/alz.13485 38011580
    [Google Scholar]
  121. Reale M. Kamal M.A. Velluto L. Gambi D. Di Nicola M. Greig N.H. Relationship between inflammatory mediators, Aβ levels and ApoE genotype in Alzheimer disease. Curr. Alzheimer Res. 2012 9 4 447 457 10.2174/156720512800492549 22272623
    [Google Scholar]
  122. Motta C. Finardi A. Toniolo S. Protective role of cerebrospinal fluid inflammatory cytokines in patients with amnestic mild cognitive impairment and early Alzheimer’s disease carrying apolipoprotein E4 genotype. J. Alzheimers Dis. 2020 76 2 681 689 10.3233/JAD‑191250 32538836
    [Google Scholar]
  123. Goikolea J. Gerenu G. Daniilidou M. Serum Thioredoxin-80 is associated with age, ApoE4, and neuropathological biomarkers in Alzheimer’s disease: A potential early sign of AD. Alzheimers Res. Ther. 2022 14 1 37 10.1186/s13195‑022‑00979‑9 35209952
    [Google Scholar]
  124. Riphagen J.M. Ramakers I.H.G.M. Freeze W.M. Linking APOE-ε4, blood-brain barrier dysfunction, and inflammation to Alzheimer’s pathology. Neurobiol. Aging 2020 85 96 103 10.1016/j.neurobiolaging.2019.09.020 31733942
    [Google Scholar]
  125. Zhang Y. Chen H. Li R. Sterling K. Song W. Amyloid β-based therapy for Alzheimer’s disease: Challenges, successes and future. Signal Transduct. Target. Ther. 2023 8 1 248 10.1038/s41392‑023‑01484‑7 37386015
    [Google Scholar]
  126. Hur J.Y. γ-Secretase in Alzheimer’s disease. Exp. Mol. Med. 2022 54 4 433 446 10.1038/s12276‑022‑00754‑8 35396575
    [Google Scholar]
  127. Carroll C.M. Li Y.M. Physiological and pathological roles of the γ-secretase complex. Brain Res. Bull. 2016 126 Pt 2 199 206 10.1016/j.brainresbull.2016.04.019 27133790
    [Google Scholar]
  128. Coric V. Salloway S. van Dyck C.H. Targeting prodromal Alzheimer disease with avagacestat: A randomized clinical trial. JAMA Neurol. 2015 72 11 1324 1333 10.1001/jamaneurol.2015.0607 26414022
    [Google Scholar]
  129. Vassar R. BACE1: The β-secretase enzyme in Alzheimer’s disease. J. Mol. Neurosci. 2004 23 1-2 105 114 10.1385/JMN:23:1‑2:105 15126696
    [Google Scholar]
  130. Agrawal M. Saraf S. Saraf S. Nose-to-brain drug delivery: An update on clinical challenges and progress towards approval of anti-Alzheimer drugs. J. Control. Release 2018 281 139 177 10.1016/j.jconrel.2018.05.011 29772289
    [Google Scholar]
  131. Nowell J. Blunt E. Gupta D. Edison P. Antidiabetic agents as a novel treatment for Alzheimer’s and Parkinson’s disease. Ageing Res. Rev. 2023 89 101979 10.1016/j.arr.2023.101979 37328112
    [Google Scholar]
  132. Benek O. Korabecny J. Soukup O. A perspective on multi-target drugs for Alzheimer’s disease. Trends Pharmacol. Sci. 2020 41 7 434 445 10.1016/j.tips.2020.04.008 32448557
    [Google Scholar]
  133. Ballard C. Aarsland D. Cummings J. Drug repositioning and repurposing for Alzheimer disease. Nat. Rev. Neurol. 2020 16 12 661 673 10.1038/s41582‑020‑0397‑4 32939050
    [Google Scholar]
  134. Huang L.K. Kuan Y.C. Lin H.W. Hu C.J. Clinical trials of new drugs for Alzheimer disease: A 2020–2023 update. J. Biomed. Sci. 2023 30 1 83 10.1186/s12929‑023‑00976‑6 37784171
    [Google Scholar]
/content/journals/cnsnddt/10.2174/0118715273382447250526062100
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β-Amyloid Pathways in Alzheimer's Disease: Mechanisms and Therapeutic Targets
Bentham Science Publishers ; https://doi.org/10.2174/0118715273382447250526062100
/content/journals/cnsnddt/10.2174/0118715273382447250526062100
/content/journals/cnsnddt/10.2174/0118715273382447250526062100
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  • Article Type:     Review Article
Keywords: Alzheimer’s disease ; mitochondrial dysfunction ; GSK3β ; β-Amyloid ; Tau ; SIRT1

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