Skip to content
2000
image of From Bench to Bedside: Cutting-Edge and Emerging Therapies for Alzheimer’s Disease

Abstract

Alzheimer’s disease (AD) remains one of the most pressing neurodegenerative disorders worldwide, with increasing prevalence and limited disease-modifying treatments. While recent clinical advances, including monoclonal antibodies like lecanemab and donanemab (early stage), show promise in slowing cognitive decline by targeting amyloid-beta pathology, their use is associated with risks such as amyloid-related imaging abnormalities (ARIA). Alongside these developments, preclinical innovations continue to explore novel mechanisms, including antisense oligonucleotides, TREM2 agonists, siRNA, mRNA-LNP platforms, and CRISPR-based gene editing. These approaches target tau aggregation, neuroinflammation, and genetic risk modifiers like APOE4. This review bridges the gap between preclinical research and clinical application by highlighting the mechanisms, therapeutic potential, and translational challenges of both established and emerging therapies. Emphasis is placed on biomarker-guided trials, model systems (, iPSC organoids), and future directions to improve efficacy, safety, and global accessibility of AD therapeutics.

Loading

Article metrics loading...

/content/journals/cnsamc/10.2174/0118715249388723250910140541
2025-09-22
2025-12-04
Loading full text...

Full text loading...

References

  1. Breijyeh Z. Karaman R. Comprehensive review on Alzheimer’s disease: causes and treatment. Molecules 2020 25 24 5789 10.3390/molecules25245789 33302541
    [Google Scholar]
  2. Rathmann K.L. Conner C.S. Alzheimer’s disease: Clinical features, pathogenesis, and treatment. Drug Intell. Clin. Pharm. 1984 18 9 684 691 10.1177/106002808401800902 6383752
    [Google Scholar]
  3. Yiannopoulou K.G. Papageorgiou S.G. Current and future treatments in Alzheimer disease: An update. J. Cent. Nerv. Syst. Dis. 2020 12 10.1177/1179573520907397 32165850
    [Google Scholar]
  4. Park J-H. Lee S-H. Alzheimer’s disease: Advances in diagnosis and treatment across the disease continuum. J. Transl. Med. 2024 22 1 159 178 [PMID: 38365731].
    [Google Scholar]
  5. Kumar A. Sidhu J. Goyal A.S. StatPearls. Treasure Island StatPearls Publishing 2020
    [Google Scholar]
  6. Eletto D. Chevet E. Argon Y. Appenzeller-Herzog C. Redox controls UPR to control redox. J. Cell Sci. 2014 127 Pt 17 3649 3658 [PMID: 25107370].
    [Google Scholar]
  7. Tepedelen B.E. Kirmizibayrak P.B. Endoplasmic reticulum-associated degradation (ERAD). Cold Spring Harb. Perspect. Biol. 2019 14 12 a041247
    [Google Scholar]
  8. Fan Y. Wang N. Rocchi A. Zhang W. Vassar R. Zhou Y. He C. Identification of natural products with neuronal and metabolic benefits through autophagy induction. Autophagy 2017 13 1 41 56 10.1080/15548627.2016.1240855 27791467
    [Google Scholar]
  9. Jain A. Lamark T. Sjøttem E. Bowitz Larsen K. Atesoh Awuh J. Øvervatn A. McMahon M. Hayes J.D. Johansen T. p62/SQSTM1 is a target gene for transcription factor NRF2 and creates a positive feedback loop by inducing antioxidant response element-driven gene transcription. J. Biol. Chem. 2010 285 29 22576 22591 10.1074/jbc.M110.118976 20452972
    [Google Scholar]
  10. Ji Z.S. Müllendorff K. Cheng I.H. Miranda R.D. Huang Y. Mahley R.W. Reactivity of apolipoprotein E4 and amyloid β peptide: Lysosomal stability and neurodegeneration. J. Biol. Chem. 2006 281 5 2683 2692 10.1074/jbc.M506646200 16298992
    [Google Scholar]
  11. Kausar S. Wang F. Cui H. The role of mitochondria in reactive oxygen species generation and its implications for neurodegenerative diseases. Cells 2018 7 12 274 10.3390/cells7120274 30563029
    [Google Scholar]
  12. Chu C.T. Autophagic stress in neuronal injury and disease. J. Neuropathol. Exp. Neurol. 2006 65 5 423 432 10.1097/01.jnen.0000229233.75253.be 16772866
    [Google Scholar]
  13. Palomo G.M. Manfredi G. Exploring new pathways of neurodegeneration in ALS: The role of mitochondria quality control. Brain Res. 2015 1607 36 46 10.1016/j.brainres.2014.09.065 25301687
    [Google Scholar]
  14. Poudel P. Park S. Recent advances in the treatment of Alzheimer’s disease using nanoparticle-based drug delivery systems. Pharmaceutics 2022 14 4 835 10.3390/pharmaceutics14040835 35456671
    [Google Scholar]
  15. Yiannopoulou K.G. Papageorgiou S.G. Current and future treatments for Alzheimer’s disease. Ther. Adv. Neurol. Disord. 2013 6 1 19 33 10.1177/1756285612461679 23277790
    [Google Scholar]
  16. Pardridge, WM Preparation of Trojan horse liposomes (THLs) for gene transfer across the blood-brain barrier William M Pardridge. Cold Spring Harb. Protoc. 2010 2010 4 10.1101/pdb.prot5407
    [Google Scholar]
  17. Lungare S. Hallam K. Badhan R.K.S. Phytochemical-loaded mesoporous silica nanoparticles for nose-to-brain olfactory drug delivery. Int. J. Pharm. 2016 513 1-2 280 293 10.1016/j.ijpharm.2016.09.042 27633279
    [Google Scholar]
  18. Kofoed R.H. Heinen S. Silburt J. Dubey S. Dibia C.L. Maes M. Simpson E.M. Hynynen K. Aubert I. Transgene distribution and immune response after ultrasound delivery of rAAV9 and PHP.B to the brain in a mouse model of amyloidosis. Mol. Ther. Methods Clin. Dev. 2021 23 390 405 10.1016/j.omtm.2021.10.001 34761053
    [Google Scholar]
  19. Morgan D. Immunotherapy for Alzheimer’s disease. J. Intern. Med. 2011 269 1 54 63 10.1111/j.1365‑2796.2010.02315.x 21158978
    [Google Scholar]
  20. Neugroschl J. Wang S. Alzheimer’s disease: Diagnosis and treatment across the spectrum of disease severity. Mt. Sinai J. Med. 2011 78 4 596 612 10.1002/msj.20279 21748748
    [Google Scholar]
  21. Dhapola R. Sarma P. Medhi B. Prakash A. Reddy D.H. Recent advances in molecular pathways and therapeutic implications targeting mitochondrial dysfunction for Alzheimer’s disease. Mol. Neurobiol. 2022 59 1 535 555 10.1007/s12035‑021‑02612‑6 34725778
    [Google Scholar]
  22. Hanger D.P. Wray S. Tau cleavage and tau aggregation in neurodegenerative disease. Biochem. Soc. Trans. 2010 38 4 1016 1020 10.1042/BST0381016 20658996
    [Google Scholar]
  23. Kimura T. Ono T. Takamatsu J. Yamamoto H. Ikegami K. Kondo A. Hasegawa M. Ihara Y. Miyamoto E. Miyakawa T. Sequential changes of tau-site-specific phosphorylation during development of paired helical filaments. Dementia 1996 7 4 177 181 [PMID: 8835879].
    [Google Scholar]
  24. Yoshida H. Goedert M. Sequential phosphorylation of tau protein by cAMP‐dependent protein kinase and SAPK4/p38δ or JNK2 in the presence of heparin generates the AT100 epitope. J. Neurochem. 2006 99 1 154 164 10.1111/j.1471‑4159.2006.04052.x 16987243
    [Google Scholar]
  25. Mayeux R. Stern Y. Epidemiology of Alzheimer disease. Cold Spring Harb. Perspect. Med. 2012 2 8 a006239 10.1101/cshperspect.a006239 22908189
    [Google Scholar]
  26. Smith J. Patel R. Zhang L. García A. Müller P. Protein homeostasis decline, aging, and Alzheimer’s disease. Mol. Neurobiol. 2024 61 7 3892 3908
    [Google Scholar]
  27. Ginsberg S.D. Hemby S.E. Lee V.M.Y. Eberwine J.H. Trojanowski J.Q. Expression profile of transcripts in Alzheimer’s disease tangle-bearing CA1 neurons. Ann. Neurol. 2000 48 1 77 87 10.1002/1531‑8249(200007)48:1<77::AID‑ANA12>3.0.CO;2‑A 10894219
    [Google Scholar]
  28. Zhou X. Li J. Wang Y. Protective effect of PDE4B subtype-specific inhibition in an AppNL-G-F Alzheimer’s disease mouse model. Neurotherapeutics 2024 21 1 113 125
    [Google Scholar]
  29. Sweeney P. Park H. Baumann M. Dunlop J. Frydman J. Kopito R. McCampbell A. Leblanc G. Venkateswaran A. Nurmi A. Hodgson R. Protein misfolding in neurodegenerative diseases: Implications and strategies. Transl. Neurodegener. 2017 6 1 6 10.1186/s40035‑017‑0077‑5 28293421
    [Google Scholar]
  30. Hardy J Selkoe DJ The Amyloid Hypothesis of Alzheimer's Disease: Progress and Problems on the Road to Therapeutics. science 2002 297 5580 353 356 10.1126/science.107299|
    [Google Scholar]
  31. Heneka M.T. Carson M.J. Khoury J.E. Landreth G.E. Brosseron F. Feinstein D.L. Jacobs A.H. Wyss-Coray T. Vitorica J. Ransohoff R.M. Herrup K. Frautschy S.A. Finsen B. Brown G.C. Verkhratsky A. Yamanaka K. Koistinaho J. Latz E. Halle A. Petzold G.C. Town T. Morgan D. Shinohara M.L. Perry V.H. Holmes C. Bazan N.G. Brooks D.J. Hunot S. Joseph B. Deigendesch N. Garaschuk O. Boddeke E. Dinarello C.A. Breitner J.C. Cole G.M. Golenbock D.T. Kummer M.P. Neuroinflammation in Alzheimer’s disease. Lancet Neurol. 2015 14 4 388 405 10.1016/S1474‑4422(15)70016‑5 25792098
    [Google Scholar]
  32. Heneka M.T. McManus R.M. Latz E. Inflammasome signalling in brain function and neurodegenerative disease. Nat. Rev. Neurosci. 2018 19 10 610 621 10.1038/s41583‑018‑0055‑7 30206330
    [Google Scholar]
  33. Kametani F. Hasegawa M. Reconsideration of amyloid hypothesis and tau hypothesis in Alzheimer’s disease. Front. Neurosci. 2018 12 25 10.3389/fnins.2018.00025 29440986
    [Google Scholar]
  34. Morawe T. Hiebel C. Kern A. Behl C. Protein homeostasis, aging and Alzheimer’s disease. Mol. Neurobiol. 2012 46 1 41 54 10.1007/s12035‑012‑8246‑0 22361852
    [Google Scholar]
  35. Gurney M.E. D’Amato E.C. Burgin A.B. Phosphodiesterase-4 (PDE4) molecular pharmacology and Alzheimer’s disease. Neurotherapeutics 2015 12 1 49 56 10.1007/s13311‑014‑0309‑7 25371167
    [Google Scholar]
  36. Balch W.E. Morimoto R.I. Dillin A. Kelly J.W. Adapting proteostasis for disease intervention. Science 2008 319 5865 916 919
    [Google Scholar]
  37. Bard F. Cannon C. Barbour R. Burke R.L. Games D. Grajeda H. Guido T. Hu K. Huang J. Johnson-Wood K. Khan K. Kholodenko D. Lee M. Lieberburg I. Motter R. Nguyen M. Soriano F. Vasquez N. Weiss K. Welch B. Seubert P. Schenk D. Yednock T. Peripherally administered antibodies against amyloid β-peptide enter the central nervous system and reduce pathology in a mouse model of Alzheimer disease. Nat. Med. 2000 6 8 916 919 10.1038/78682 10932230
    [Google Scholar]
  38. Belinson H. Lev D. Masliah E. Michaelson D.M. Activation of the amyloid cascade in apolipoprotein E4 transgenic mice induces lysosomal activation and neurodegeneration resulting in marked cognitive deficits. J. Neurosci. 2008 28 18 4690 4701 10.1523/JNEUROSCI.5633‑07.2008 18448646
    [Google Scholar]
  39. Noble W. Hanger D.P. Miller C.C.J. Lovestone S. The importance of tau phosphorylation for neurodegenerative diseases. Front. Neurol. 2013 4 83 10.3389/fneur.2013.00083 23847585
    [Google Scholar]
  40. Congdon E.E. Sigurdsson E.M. Tau-targeting therapies for Alzheimer disease. Nat. Rev. Neurol. 2018 14 7 399 415 10.1038/s41582‑018‑0013‑z 29895964
    [Google Scholar]
  41. Deger J.M. Gerson J.E. Kayed R. The interrelationship of proteasome impairment and oligomeric intermediates in neurodegeneration. Aging Cell 2015 14 5 715 724 10.1111/acel.12359 26053162
    [Google Scholar]
  42. Casley C.S. Canevari L. Land J.M. Clark J.B. Sharpe M.A. β‐Amyloid inhibits integrated mitochondrial respiration and key enzyme activities. J. Neurochem. 2002 80 1 91 100 10.1046/j.0022‑3042.2001.00681.x 11796747
    [Google Scholar]
  43. Krencik R. Weick J.P. Liu Y. Zhang Z.J. Zhang S.C. Specification of transplantable astroglial subtypes from human pluripotent stem cells. Nat. Biotechnol. 2011 29 6 528 534 10.1038/nbt.1877 21602806
    [Google Scholar]
  44. Kunkle B.W. Grenier-Boley B. Sims R. Bis J.C. Damotte V. Naj A.C. Boland A. Vronskaya M. van der Lee S.J. Amlie-Wolf A. Bellenguez C. Frizatti A. Chouraki V. Martin E.R. Sleegers K. Badarinarayan N. Jakobsdottir J. Hamilton-Nelson K.L. Moreno-Grau S. Olaso R. Raybould R. Chen Y. Kuzma A.B. Hiltunen M. Morgan T. Ahmad S. Vardarajan B.N. Epelbaum J. Hoffmann P. Boada M. Beecham G.W. Garnier J.G. Harold D. Fitzpatrick A.L. Valladares O. Moutet M.L. Gerrish A. Smith A.V. Qu L. Bacq D. Denning N. Jian X. Zhao Y. Del Zompo M. Fox N.C. Choi S.H. Mateo I. Hughes J.T. Adams H.H. Malamon J. Sanchez-Garcia F. Patel Y. Brody J.A. Dombroski B.A. Naranjo M.C.D. Daniilidou M. Eiriksdottir G. Mukherjee S. Wallon D. Uphill J. Aspelund T. Cantwell L.B. Garzia F. Galimberti D. Hofer E. Butkiewicz M. Fin B. Scarpini E. Sarnowski C. Bush W.S. Meslage S. Kornhuber J. White C.C. Song Y. Barber R.C. Engelborghs S. Sordon S. Voijnovic D. Adams P.M. Vandenberghe R. Mayhaus M. Cupples L.A. Albert M.S. De Deyn P.P. Gu W. Himali J.J. Beekly D. Squassina A. Hartmann A.M. Orellana A. Blacker D. Rodriguez-Rodriguez E. Lovestone S. Garcia M.E. Doody R.S. Munoz-Fernadez C. Sussams R. Lin H. Fairchild T.J. Benito Y.A. Holmes C. Karamujić-Čomić H. Frosch M.P. Thonberg H. Maier W. Roshchupkin G. Ghetti B. Giedraitis V. Kawalia A. Li S. Huebinger R.M. Kilander L. Moebus S. Hernández I. Kamboh M.I. Brundin R. Turton J. Yang Q. Katz M.J. Concari L. Lord J. Beiser A.S. Keene C.D. Helisalmi S. Kloszewska I. Kukull W.A. Koivisto A.M. Lynch A. Tarraga L. Larson E.B. Haapasalo A. Lawlor B. Mosley T.H. Lipton R.B. Solfrizzi V. Gill M. Longstreth W.T. Montine T.J. Frisardi V. Diez-Fairen M. Rivadeneira F. Petersen R.C. Deramecourt V. Alvarez I. Salani F. Ciaramella A. Boerwinkle E. Reiman E.M. Fievet N. Rotter J.I. Reisch J.S. Hanon O. Cupidi C. Andre Uitterlinden A.G. Royall D.R. Dufouil C. Maletta R.G. de Rojas I. Sano M. Brice A. Cecchetti R. George-Hyslop P.S. Ritchie K. Tsolaki M. Tsuang D.W. Dubois B. Craig D. Wu C.K. Soininen H. Avramidou D. Albin R.L. Fratiglioni L. Germanou A. Apostolova L.G. Keller L. Koutroumani M. Arnold S.E. Panza F. Gkatzima O. Asthana S. Hannequin D. Whitehead P. Atwood C.S. Caffarra P. Hampel H. Quintela I. Carracedo Á. Lannfelt L. Rubinsztein D.C. Barnes L.L. Pasquier F. Frölich L. Barral S. McGuinness B. Beach T.G. Johnston J.A. Becker J.T. Passmore P. Bigio E.H. Schott J.M. Bird T.D. Warren J.D. Boeve B.F. Lupton M.K. Bowen J.D. Proitsi P. Boxer A. Powell J.F. Burke J.R. Kauwe J.S.K. Burns J.M. Mancuso M. Buxbaum J.D. Bonuccelli U. Cairns N.J. McQuillin A. Cao C. Livingston G. Carlson C.S. Bass N.J. Carlsson C.M. Hardy J. Carney R.M. Bras J. Carrasquillo M.M. Guerreiro R. Allen M. Chui H.C. Fisher E. Masullo C. Crocco E.A. DeCarli C. Bisceglio G. Dick M. Ma L. Duara R. Graff-Radford N.R. Evans D.A. Hodges A. Faber K.M. Scherer M. Fallon K.B. Riemenschneider M. Fardo D.W. Heun R. Farlow M.R. Kölsch H. Ferris S. Leber M. Foroud T.M. Heuser I. Galasko D.R. Giegling I. Gearing M. Hüll M. Geschwind D.H. Gilbert J.R. Morris J. Green R.C. Mayo K. Growdon J.H. Feulner T. Hamilton R.L. Harrell L.E. Drichel D. Honig L.S. Cushion T.D. Huentelman M.J. Hollingworth P. Hulette C.M. Hyman B.T. Marshall R. Jarvik G.P. Meggy A. Abner E. Menzies G.E. Jin L.W. Leonenko G. Real L.M. Jun G.R. Baldwin C.T. Grozeva D. Karydas A. Russo G. Kaye J.A. Kim R. Jessen F. Kowall N.W. Vellas B. Kramer J.H. Vardy E. LaFerla F.M. Jöckel K.H. Lah J.J. Dichgans M. Leverenz J.B. Mann D. Levey A.I. Pickering-Brown S. Lieberman A.P. Klopp N. Lunetta K.L. Wichmann H.E. Lyketsos C.G. Morgan K. Marson D.C. Brown K. Martiniuk F. Medway C. Mash D.C. Nöthen M.M. Masliah E. Hooper N.M. McCormick W.C. Daniele A. McCurry S.M. Bayer A. McDavid A.N. Gallacher J. McKee A.C. van den Bussche H. Mesulam M. Brayne C. Miller B.L. Riedel-Heller S. Miller C.A. Miller J.W. Al-Chalabi A. Morris J.C. Shaw C.E. Myers A.J. Wiltfang J. O’Bryant S. Olichney J.M. Alvarez V. Parisi J.E. Singleton A.B. Paulson H.L. Collinge J. Perry W.R. Mead S. Peskind E. Cribbs D.H. Rossor M. Pierce A. Ryan N.S. Poon W.W. Nacmias B. Potter H. Sorbi S. Quinn J.F. Sacchinelli E. Raj A. Spalletta G. Raskind M. Caltagirone C. Bossù P. Orfei M.D. Reisberg B. Clarke R. Reitz C. Smith A.D. Ringman J.M. Warden D. Roberson E.D. Wilcock G. Rogaeva E. Bruni A.C. Rosen H.J. Gallo M. Rosenberg R.N. Ben-Shlomo Y. Sager M.A. Mecocci P. Saykin A.J. Pastor P. Cuccaro M.L. Vance J.M. Schneider J.A. Schneider L.S. Slifer S. Seeley W.W. Smith A.G. Sonnen J.A. Spina S. Stern R.A. Swerdlow R.H. Tang M. Tanzi R.E. Trojanowski J.Q. Troncoso J.C. Van Deerlin V.M. Van Eldik L.J. Vinters H.V. Vonsattel J.P. Weintraub S. Welsh-Bohmer K.A. Wilhelmsen K.C. Williamson J. Wingo T.S. Woltjer R.L. Wright C.B. Yu C.E. Yu L. Saba Y. Pilotto A. Bullido M.J. Peters O. Crane P.K. Bennett D. Bosco P. Coto E. Boccardi V. De Jager P.L. Lleo A. Warner N. Lopez O.L. Ingelsson M. Deloukas P. Cruchaga C. Graff C. Gwilliam R. Fornage M. Goate A.M. Sanchez-Juan P. Kehoe P.G. Amin N. Ertekin-Taner N. Berr C. Debette S. Love S. Launer L.J. Younkin S.G. Dartigues J.F. Corcoran C. Ikram M.A. Dickson D.W. Nicolas G. Campion D. Tschanz J. Schmidt H. Hakonarson H. Clarimon J. Munger R. Schmidt R. Farrer L.A. Van Broeckhoven C. C O’Donovan M. DeStefano A.L. Jones L. Haines J.L. Deleuze J.F. Owen M.J. Gudnason V. Mayeux R. Escott-Price V. Psaty B.M. Ramirez A. Wang L.S. Ruiz A. van Duijn C.M. Holmans P.A. Seshadri S. Williams J. Amouyel P. Schellenberg G.D. Lambert J.C. Pericak-Vance M.A. Genetic meta-analysis of diagnosed Alzheimer’s disease identifies new risk loci and implicates Aβ, tau, immunity and lipid processing. Nat. Genet. 2019 51 3 414 430 10.1038/s41588‑019‑0358‑2 30820047
    [Google Scholar]
  45. Wang X. Liu Y. Zhang L. Chen J. Hu Z. Li Y. Oxidative stress and amyloid β-peptides in Alzheimer’s disease: revisited mechanisms and emerging targets. Front. Neurol. 2025 16 1550709
    [Google Scholar]
  46. Choi H. Park H.H. Lee K.Y. Choi N.Y. Yu H.J. Lee Y.J. Park J. Huh Y.M. Lee S.H. Koh S.H. Coenzyme Q10 restores amyloid beta-inhibited proliferation of neural stem cells by activating the PI3K pathway. Stem Cells Dev. 2013 22 15 2112 2120 10.1089/scd.2012.0604 23509892
    [Google Scholar]
  47. Christianson J.C. Ye Y. Cleaning up in the endoplasmic reticulum: Ubiquitin in charge. Nat. Struct. Mol. Biol. 2014 21 4 325 335 10.1038/nsmb.2793 24699081
    [Google Scholar]
  48. Vossel K.A. Zhang K. Brodbeck J. Daub A.C. Sharma P. Finkbeiner S. Cui B. Mucke L. Tau reduction prevents Abeta-induced defects in axonal transport. Science 2010 330 6001 198 10.1126/science.1194653 20829454
    [Google Scholar]
  49. Huat T.J. Camats-Perna J. Newcombe E.A. Valmas N. Kitazawa M. Medeiros R. Metal toxicity links to Alzheimer’s disease and neuroinflammation. J. Mol. Biol. 2019 431 9 1843 1868 10.1016/j.jmb.2019.01.018 30664867
    [Google Scholar]
  50. Patel D. McAllister S.L. Teckman J.H. Residue‐level profiling of GRP94 function in alpha-1-antitrypsin deficiency using Gaussian process spatial covariance. Nat. Commun. 2024 15 1200
    [Google Scholar]
  51. Christianson J.C. Shaler T.A. Tyler R.E. Kopito R.R. OS-9 and GRP94 deliver mutant α1-antitrypsin to the Hrd1–SEL1L ubiquitin ligase complex for ERAD. Nat. Cell Biol. 2008 10 3 272 282 10.1038/ncb1689 18264092
    [Google Scholar]
  52. Bordi M. Berg M.J. Mohan P.S. Peterhoff C.M. Alldred M.J. Che S. Ginsberg S.D. Nixon R.A. Autophagy flux in CA1 neurons of Alzheimer hippocampus: Increased induction overburdens failing lysosomes to propel neuritic dystrophy. Autophagy 2016 12 12 2467 2483 10.1080/15548627.2016.1239003 27813694
    [Google Scholar]
  53. Piras A. Collin L. Grüninger F. Graff C. Rönnbäck A. Autophagic and lysosomal defects in human tauopathies: analysis of post-mortem brain from patients with familial Alzheimer disease, corticobasal degeneration and progressive supranuclear palsy. Acta Neuropathol. Commun. 2016 4 1 22 10.1186/s40478‑016‑0292‑9 26936765
    [Google Scholar]
  54. Yu W.H. Cuervo A.M. Kumar A. Peterhoff C.M. Schmidt S.D. Lee J.H. Mohan P.S. Mercken M. Farmery M.R. Tjernberg L.O. Jiang Y. Duff K. Uchiyama Y. Näslund J. Mathews P.M. Cataldo A.M. Nixon R.A. Macroautophagy—a novel β-amyloid peptide-generating pathway activated in Alzheimer’s disease. J. Cell Biol. 2005 171 1 87 98 10.1083/jcb.200505082 16203860
    [Google Scholar]
  55. Lin C.L. Cheng Y.S. Li H.H. Chiu P.Y. Chang Y.T. Ho Y.J. Lai T.J. Amyloid-β suppresses AMP-activated protein kinase (AMPK) signaling and contributes to α-synuclein-induced cytotoxicity. Exp. Neurol. 2016 275 Pt 1 84 98 10.1016/j.expneurol.2015.10.009 26515689
    [Google Scholar]
  56. Park H. Kam T.I. Kim Y. Choi H. Gwon Y. Kim C. Koh J.Y. Jung Y.K. Neuropathogenic role of adenylate kinase-1 in Aβ-mediated tau phosphorylation via AMPK and GSK3β. Hum. Mol. Genet. 2012 21 12 2725 2737 10.1093/hmg/dds100 22419736
    [Google Scholar]
  57. Wang Y. Mandelkow E. Degradation of tau protein by autophagy and proteasomal pathways. Biochem. Soc. Trans. 2012 40 4 644 652 10.1042/BST20120071 22817709
    [Google Scholar]
  58. Mori H. Kondo J. Ihara Y. Ubiquitin is a component of paired helical filaments in Alzheimer’s disease. Science 1987 235 4796 1641 1644 10.1126/science.3029875 3029875
    [Google Scholar]
  59. Perry G. Friedman R. Shaw G. Chau V. Ubiquitin is detected in neurofibrillary tangles and senile plaque neurites of Alzheimer disease brains. Proc. Natl. Acad. Sci. USA 1987 84 9 3033 3036 10.1073/pnas.84.9.3033 3033674
    [Google Scholar]
  60. Tell V. Hilgeroth A. Recent developments of protein kinase inhibitors as potential AD therapeutics. Front. Cell. Neurosci. 2013 7 189 10.3389/fncel.2013.00189 24312003
    [Google Scholar]
  61. Yarza R. Vela S. Solas M. Ramirez M.J. c-Jun N-terminal kinase (JNK) signaling as a therapeutic target for Alzheimer’s disease. Front. Pharmacol. 2016 6 321 10.3389/fphar.2015.00321 26793112
    [Google Scholar]
  62. Ruiz-Pérez G. Ruiz de Martín Esteban S. Marqués S. Aparicio N. Grande M.T. Benito-Cuesta I. Martínez-Relimpio A.M. Arnanz M.A. Tolón R.M. Posada-Ayala M. Cravatt B.F. Esteban J.A. Romero J. Palenzuela R. Potentiation of amyloid beta phagocytosis and amelioration of synaptic dysfunction upon FAAH deletion in a mouse model of Alzheimer’s disease. J. Neuroinflammation 2021 18 1 223 10.1186/s12974‑021‑02276‑y 34587978
    [Google Scholar]
  63. Long C. Fritts A. Broadway J. Brawman-Mintzer O. Mintzer J. Neuroinflammation: A driving force in the onset and progression of Alzheimer’s disease. J. Clin. Med. 2025 14 2 331 10.3390/jcm14020331 39860337
    [Google Scholar]
  64. Yokokura M. Mori N. Yagi S. Yoshikawa E. Kikuchi M. Yoshihara Y. Wakuda T. Sugihara G. Takebayashi K. Suda S. Iwata Y. Ueki T. Tsuchiya K.J. Suzuki K. Nakamura K. Ouchi Y. In vivo changes in microglial activation and amyloid deposits in brain regions with hypometabolism in Alzheimer’s disease. Eur. J. Nucl. Med. Mol. Imaging 2011 38 2 343 351 10.1007/s00259‑010‑1612‑0 20844871
    [Google Scholar]
  65. Kechko O.I. Petrushanko I.Y. Brower C.S. Adzhubei A.A. Moskalev A.A. Piatkov K.I. Mitkevich V.A. Makarov A.A. Beta-amyloid induces apoptosis of neuronal cells by inhibition of the Arg/N-end rule pathway proteolytic activity. Aging 2019 11 16 6134 6152 10.18632/aging.102177 31446431
    [Google Scholar]
  66. Llanos-González E. Henares-Chavarino Á.A. Pedrero-Prieto C.M. García-Carpintero S. Frontiñán-Rubio J. Sancho-Bielsa F.J. Alcain F.J. Peinado J.R. Rabanal-Ruíz Y. Durán-Prado M. Interplay between mitochondrial oxidative disorders and proteostasis in Alzheimer’s disease. Front. Neurosci. 2020 13 1444 10.3389/fnins.2019.01444 32063825
    [Google Scholar]
  67. Bhat A.H. Dar K.B. Anees S. Zargar M.A. Masood A. Sofi M.A. Ganie S.A. Oxidative stress, mitochondrial dysfunction and neurodegenerative diseases; a mechanistic insight. Biomed. Pharmacother. 2015 74 101 110 10.1016/j.biopha.2015.07.025 26349970
    [Google Scholar]
  68. Cheignon C. Tomas M. Bonnefont-Rousselot D. Faller P. Hureau C. Collin F. Oxidative stress and the amyloid beta peptide in Alzheimer’s disease. Redox Biol. 2018 14 450 464 10.1016/j.redox.2017.10.014 29080524
    [Google Scholar]
  69. Lyra e Silva N.M. Gonçalves R.A. Boehnke S.E. Forny-Germano L. Munoz D.P. De Felice F.G. Understanding the link between insulin resistance and Alzheimer’s disease: Insights from animal models. Exp. Neurol. 2019 316 1 11 10.1016/j.expneurol.2019.03.016
    [Google Scholar]
  70. Moreno-Gonzalez I. Soto C. Natural animal models of neurodegenerative protein misfolding diseases. Curr. Pharm. Des. 2012 18 8 1148 1158 10.2174/138161212799315768 22288404
    [Google Scholar]
  71. Martini A.C. Forner S. Trujillo-Estrada L. Baglietto-Vargas D. LaFerla F.M. Past to future: What animal models have taught us about Alzheimer’s disease. J. Alzheimers Dis. 2018 64 s1 S365 S378 10.3233/JAD‑179917 29504540
    [Google Scholar]
  72. LaFerla F.M. Green K.N. Animal models of Alzheimer disease. Cold Spring Harb. Perspect. Med. 2012 2 11 a006320 10.1101/cshperspect.a006320 23002015
    [Google Scholar]
  73. King A. The search for better animal models of Alzheimer’s disease. Nature 2018 559 7715 S13 S15 10.1038/d41586‑018‑05722‑9 30046083
    [Google Scholar]
  74. Trujillo-Estrada L. Sanchez-Mejias E. Sanchez-Varo R. Garcia-Leon J.A. Nuñez-Diaz C. Davila J.C. Vitorica J. LaFerla F.M. Moreno-Gonzalez I. Gutierrez A. Baglietto-Vargas D. Animal and cellular models of Alzheimer’s disease: Progress, promise, and future approaches. Neuroscientist 2022 28 6 572 593 10.1177/10738584211001753 33769131
    [Google Scholar]
  75. Grant W.B. Campbell A. Itzhaki R.F. Savory J. The significance of environmental factors in the etiology of Alzheimer’s disease. J. Alzheimers Dis. 2002 4 3 179 189 10.3233/JAD‑2002‑4308 12226537
    [Google Scholar]
  76. Manzano S. González J. Marcos A. Payno M. Villanueva C. Matías-Guiu J. Modelos experimentales de la enfermedad de Alzheimer. Neurología 2009 24 4 255 262 [PMID: 19603296].
    [Google Scholar]
  77. Games D. Adams D. Alessandrini R. Barbour R. Borthelette P. Blackwell C. Carr T. Clemens J. Donaldson T. Gillespie F. Guido T. Hagopian S. Johnson-Wood K. Khan K. Lee M. Leibowitz P. Lieberburg I. Little S. Masliah E. McConlogue L. Montoya-Zavala M. Mucke L. Paganini L. Penniman E. Power M. Schenk D. Seubert P. Snyder B. Soriano F. Tan H. Vitale J. Wadsworth S. Wolozin B. Zhao J. Alzheimer-type neuropathology in transgenic mice overexpressing V717F β-amyloid precursor protein. Nature 1995 373 6514 523 527 10.1038/373523a0 7845465
    [Google Scholar]
  78. Drummond E. Wisniewski T. Alzheimer’s disease: Experimental models and reality. Acta Neuropathol. 2017 133 2 155 175 10.1007/s00401‑016‑1662‑x 28025715
    [Google Scholar]
  79. DeVos S.L. Miller R.L. Schoch K.M. Holmes B.B. Kebodeaux C.S. Wegener A.J. Chen G. Shen T. Tran H. Nichols B. Zanardi T.A. Kordasiewicz H.B. Swayze E.E. Bennett C.F. Diamond M.I. Miller T.M. Tau reduction prevents neuronal loss and reverses pathological tau deposition and seeding in mice with tauopathy. Sci. Transl. Med. 2017 9 374 eaag0481 10.1126/scitranslmed.aag0481 28123067
    [Google Scholar]
  80. Wang S. Mustafa M. Yuede C.M. Salazar S.V. Kong P. Long H. Ward M. Siddiqui O. Paul R. Gilfillan S. Ibrahim A. Rhinn H. Tassi I. Rosenthal A. Schwabe T. Colonna M. Anti-human TREM2 induces microglia proliferation and reduces pathology in an Alzheimer’s disease model. J. Exp. Med. 2020 217 9 e20200785 10.1084/jem.20200785 32579671
    [Google Scholar]
  81. Novak P. Schmidt R. Kontsekova E. Tau therapeutic pipeline: Outlook on the most promising pharmacological strategies for Alzheimer’s disease. Front. Aging Neurosci. 2020 12 561398
    [Google Scholar]
  82. Afsharinejad Z. Pourhanifeh M.H. Zarezadeh M. Jaleel S.A. Khan H. Javadinia S.A. Lipid-based mRNA delivery systems for neurodegenerative disease therapy. Pharmaceutics 2022 14 3 523 [PMID: 35335899].
    [Google Scholar]
  83. György B. Lööv C. Zaborowski M.P. Takeda S. Kleinsmith S. Parker B. Dassie J.P. Balaj L. Noske A. Misic A. Hochberg F.H. CRISPR/Cas9 mediated disruption of amyloid precursor protein gene reduces amyloid beta generation. Mol. Ther. Nucleic Acids 2018 11 488 497
    [Google Scholar]
  84. Umeda T. Maekawa S. Kimura T. Takashima A. Tomiyama T. Mori H. Neurofibrillary tangle formation by introducing wild-type human tau into APP transgenic mice. Acta Neuropathol. 2014 127 5 685 698 10.1007/s00401‑014‑1259‑1 24531886
    [Google Scholar]
  85. Calissano P. Matrone C. Amadoro G. Apoptosis and in vitro Alzheimer’s disease neuronal models. Commun. Integr. Biol. 2009 2 2 163 169 10.4161/cib.7704 19513272
    [Google Scholar]
  86. Galli C. Piccini A. Ciotti M.T. Castellani L. Calissano P. Zaccheo D. Tabaton M. Increased amyloidogenic secretion in cerebellar granule cells undergoing apoptosis. Proc. Natl. Acad. Sci. USA 1998 95 3 1247 1252 10.1073/pnas.95.3.1247 9448317
    [Google Scholar]
  87. Piccini A. Ciotti M.T. Vitolo O.V. Calissano P. Tabaton M. Galli C. Endogenous APP derivatives oppositely modulate apoptosis through an autocrine loop. Neuroreport 2000 11 7 1375 1379 10.1097/00001756‑200005150‑00005 10841341
    [Google Scholar]
  88. Salehi A. Verhaagen J. Dijkhuizen P.A. Swaab D.F. Co-localization of high-affinity neurotrophin receptors in nucleus basalis of Meynert neurons and their differential reduction in Alzheimer’s disease. Neuroscience 1996 75 2 373 387 10.1016/0306‑4522(96)00273‑4 8931004
    [Google Scholar]
  89. Costantini C. Scrable H. Puglielli L. An aging pathway controls the TrkA to p75NTR receptor switch and amyloid β-peptide generation. EMBO J. 2006 25 9 1997 2006 10.1038/sj.emboj.7601062 16619032
    [Google Scholar]
  90. Canu N. Calissano P. In vitro cultured neurons for molecular studies correlating apoptosis with events related to Alzheimer disease. Cerebellum 2003 2 4 270 278 10.1080/14734220310004289 14964686
    [Google Scholar]
  91. Leuzy A. Heurling K. Ashton N.J. Schöll M. Zimmer E.R. Focus: medical technology: In vivo detection of Alzheimer’s disease. Yale J. Biol. Med. 2018 91 3 291 300 [PMID: 30258316].
    [Google Scholar]
  92. Nakamura A. Kaneko N. Villemagne V.L. Kato T. Doecke J. Doré V. Fowler C. Li Q.X. Martins R. Rowe C. Tomita T. Matsuzaki K. Ishii K. Ishii K. Arahata Y. Iwamoto S. Ito K. Tanaka K. Masters C.L. Yanagisawa K. High performance plasma amyloid-β biomarkers for Alzheimer’s disease. Nature 2018 554 7691 249 254 10.1038/nature25456 29420472
    [Google Scholar]
  93. Frisoni G.B. Bocchetta M. Chételat G. Rabinovici G.D. de Leon M.J. Kaye J. Reiman E.M. Scheltens P. Barkhof F. Black S.E. Brooks D.J. Carrillo M.C. Fox N.C. Herholz K. Nordberg A. Jack C.R. Jagust W.J. Johnson K.A. Rowe C.C. Sperling R.A. Thies W. Wahlund L.O. Weiner M.W. Pasqualetti P. DeCarli C. Imaging markers for Alzheimer disease. Neurology 2013 81 5 487 500 10.1212/WNL.0b013e31829d86e8 23897875
    [Google Scholar]
  94. Mattsson N. Smith R. Strandberg O. Palmqvist S. Schöll M. Insel P.S. Hägerström D. Ohlsson T. Zetterberg H. Blennow K. Jögi J. Hansson O. Comparing 18 F-AV-1451 with CSF t-tau and p-tau for diagnosis of Alzheimer disease. Neurology 2018 90 5 e388 e395 10.1212/WNL.0000000000004887 29321235
    [Google Scholar]
  95. Li, Misfolding and aggregation in neurodegenerative diseases: protein clearance mechanisms and therapeutic strategies. Cell. Mol. Neurobiol. 2023 44 5 123 145
    [Google Scholar]
  96. Zhang, Stress dynamically modulates neuronal autophagy to gate depression-related plasticity. Nature 2025
    [Google Scholar]
/content/journals/cnsamc/10.2174/0118715249388723250910140541
Loading
/content/journals/cnsamc/10.2174/0118715249388723250910140541
Loading

Data & Media loading...

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test