SavedAdd your journal

Journals / Osmangazi Tıp Dergisi / 2026 / Cilt: 48 Sayı: Öğrenci Özel Sayısı 2026

The Dual Nature of Aβ and Tau in Alzheimer's Disease: Synaptic Pruning, Actin Dysfunction, and Homeostatic Restoration

Alzheimer Hastalığında Aβ ve Tau'nun İkili Doğası: Sinaptik Budama, Aktin Disfonksiyonu ve Homeostatik Restorasyon

Hilal Karakurt(ESKISEHIR OSMANGAZI UNIVERSITY, ESKİŞEHİR HEALTH ACADEMY)0009-0005-5778-7910
Merve Yunak(ESKISEHIR OSMANGAZI UNIVERSITY, ESKİŞEHİR HEALTH ACADEMY)0009-0002-0320-0713
Fahrettin Afşin Sarı(ESKISEHIR OSMANGAZI UNIVERSITY, ESKİŞEHİR HEALTH ACADEMY)0009-0006-3176-4195
Aybars Kökce(ESKİŞEHİR OSMANGAZİ ÜNİVERSİTESİ, TIP FAKÜLTESİ)0000-0002-2389-468X
Pages
9–17
Publication Date
2026-08-14
🏛️Bibliographic metadata and full text access for this article are provided via DergiPark.
DergiPark Record ↗
✨

AI Summary & Key Takeaways

AI Insight
⚡ TL;DR(Too Long; Didn't Read)

Conclusion: Effective disease-modifying therapies require abandoning indiscriminate protein clearance in favour of "homeostatic restoration" preserving actin-microtubule fluidity and protecting synaptic function from aberrant microglial engulfment.

📌 3 Key Takeaways

🎯
Objective & Hypothesis:The biochemical paradigm of Alzheimer's Disease (AD) is shifting from the amyloid cascade hypothesis toward a more nuanced "homeostatic collapse" framework.
📊
Key Findings & Data:This structural decay tags compromised synapses with C1q, co-opting the microglial pruning machinery and driving neuroinflammation via inflammasome activation.
💡
Conclusion & Impact:Conclusion: Effective disease-modifying therapies require abandoning indiscriminate protein clearance in favour of "homeostatic restoration" preserving actin-microtubule fluidity and protecting synaptic function from aberrant microglial engulfment.
🔬Design:Review & Systematic Survey
📍Scope:Comprehensive Sample
⚙️Variables:Alzheimer hastalığı · Amiloid beta · Tau proteini

Abstract

The biochemical paradigm of Alzheimer's Disease (AD) is shifting from the amyloid cascade hypothesis toward a more nuanced "homeostatic collapse" framework. This review critically examines the physiological roles of Amyloid Beta (Aβ) and Tau as essential regulators of innate immunity, metabolic homeostasis, and synaptic plasticity. Under pathological conditions, hyperphosphorylated Tau and Aβ oligomers synergistically destabilize the actin-microtubule axis, forming static cofilin-actin rods that silence synapses. This structural decay tags compromised synapses with C1q, co-opting the microglial pruning machinery and driving neuroinflammation via inflammasome activation. Conclusion: Effective disease-modifying therapies require abandoning indiscriminate protein clearance in favour of "homeostatic restoration" preserving actin-microtubule fluidity and protecting synaptic function from aberrant microglial engulfment.

Özet

Alzheimer Hastalığının (AH) paradigması, geleneksel amiloid kaskad hipotezinden "homeostatik çöküş" anlayışına kaymaktadır. Bu derleme, doğal immünite, metabolik homeostaz ve sinaptik plastisitenin düzenleyicileri olan Amiloid Beta (Aβ) ve Mikrotübül İlişkili Protein Tau'nun fizyolojik rollerinden patolojik sürece dahil olma mekanizmalarını incelemektedir. Patolojik koşullarda hiperfosforile Tau ile Aβ oligomerleri arasındaki sinerjik etkileşim, aktin-mikrotübül aksını destabilize eder; statik kofilin-aktin çubuklarının oluşumu ve aktin "treadmilling" döngüsünün durmasıyla sinaptik susma gerçekleşir. Bu yapısal çöküş, hasarlı sinapsları C1q ile işaretleyerek mikroglial budama mekanizmasını bozar ve inflamazom aktivasyonu yoluyla nöroenflamasyonu sürdürür. Sonuç: AH’nda etkili tedaviler için patogenezdeki rollerine rağmen ayrım gözetmeden bu proteinlerin temizlenmesi yaklaşımından vazgeçilmeli; aktin-mikrotübül iskeletinin dinamik akışkanlığını koruyan "homeostatik restorasyon" stratejileri önceliklendirilmelidir.

🔖

Cite This Article

Karakurt, H., Yunak, M., Sarı, F. A., Kökce, A. (2026). The Dual Nature of Aβ and Tau in Alzheimer's Disease: Synaptic Pruning, Actin Dysfunction, and Homeostatic Restoration. Osmangazi Tıp Dergisi, Cilt: 48 Sayı: Öğrenci Özel Sayısı 2026, 9–17. https://doi.org/10.20515/otd.1963013

📄 Full Text PDF Viewer

📄

PDF görüntüleyici hazırlanıyor...

References (30)

  1. Imbimbo BP, Ippati S, Watling M. Should drug discovery scientists still embrace the amyloid hypothesis for Alzheimer's disease or should they be looking elsewhere? Expert Opin Drug Discov. 2020;15(11):1241-1251.
  2. Kent SA, Spires-Jones TL, Bhatt DL. The physiological roles of tau and Aβ: implications for Alzheimer's disease pathology and therapeutics. Acta Neuropathol. 2020;140(4):417-447.
  3. Baethge C, Goldbeck-Wood S, Mertens S. SANRA-a scale for the quality assessment of narrative review articles. Res Integr Peer Rev. 2019;4:5.
  4. Barbier P, Zejneli O, Martinho M, Lasorsa A, Belle V, Smet-Nocca C, et al. Role of Tau as a Microtubule-Associated Protein: Structural and Functional Aspects. Front Aging Neurosci. 2019;11:204.
  5. Violet M, Delattre L, Tardivel M, A'ali A, Chauderlier A, Caillierez R, et al. A major role for Tau in neuronal DNA and RNA protection in vivo under physiological and hyper-excitation conditions. Front Cell Neurosci. 2014;8:84.
  6. Lei P, Ayton S, Finkelstein DI, Spoerri L, Ciccotosto GD, Wright DK, et al. Tau deficiency induces parkinsonism with dementia by impairing iron export. Nat Med. 2012;18(2):291-295.
  7. Marciniak E, Leboucher A, Caron E, Ahmed T, Tailleux A, Dumont J, et al. Tau deletion promotes brain insulin resistance. J Exp Med. 2017;214(8):2257-2269.
  8. Ludewig S, Korte M. Novel insights into the physiological function of the APP gene family and its proteolytic fragments in synaptic plasticity. Front Mol Neurosci. 2017;9:161.
  9. Egan MF, Kost J, Voss T, Mukai Y, Aisen PS, Cummings JL, et al. Randomized Trial of Verubecestat for Prodromal Alzheimer's Disease. N Engl J Med. 2019;380(15):1408-1420.
  10. Moir RD, Lathe R, Tanzi RE. The antimicrobial protection hypothesis of Alzheimer's disease. Alzheimers Dement. 2018;14(12):1602-1614.
  11. Sims JR, Zimmer JA, Evans CD, Lu M, Ardayfio P, Sparks J, et al. Donanemab in Early Symptomatic Alzheimer Disease: The TRAILBLAZER-ALZ 2 Randomized Clinical Trial. JAMA. 2023;330(6):512-527.
  12. Spence EF, Soderling SH. Actin out: regulation of the synaptic cytoskeleton. J Biol Chem. 2013;288(30):21387-21395.
  13. Bamburg JR, Bernstein BW. Actin dynamics and cofilin-actin rods in Alzheimer disease. Cytoskeleton. 2016;73(9):477-497.
  14. Davis RC, Marsden IT, Maloney MT, Minamide LS, Bamburg JR. Amyloid beta dimers/trimers potently induce cofilin-actin rods. Mol Neurodegener. 2011;6:10.
  15. Zhuravlev, A.V. Neuronal Actin Remodeling and Its Role in Higher Nervous Activity. Int. J. Mol. Sci. 2025, 26, 11215. https://doi.org/10.3390/ijms262211215
  16. Dejanovic B, Huntley MA, De Mazière A, Meilandt WJ, Wu T, Srinivasan K, et al. Changes in the synaptic proteome in tauopathy and rescue of synapse loss by C1q antibodies. Neuron. 2018;100(6):1322-1336.
  17. Wen Q, Mustafi SM, Li J, Risacher SL, Tallman EF, Brown SA, et al. Tau-related white-matter alterations along spatially selective pathways. NeuroImage. 2021;226:117560.
  18. Taylor HBC, Emptage NJ, Jeans AF. Long-term depression links amyloid-β to the pathological hyperphosphorylation of tau. Cell Rep. 2021 Aug 31;36(9):109638.
  19. Rush T, Martinez-Hernandez J, Dollmeyer M, Frandemiche ML et al. Synaptotoxicity in Alzheimer's Disease Involved a Dysregulation of Actin Cytoskeleton Dynamics through Cofilin 1 Phosphorylation. J Neurosci. 2018 Nov 28;38(48):10349-10361.
  20. Fulga TA, Elson-Schwab I, Khurana V, Steinhilb ML, Spires TL et al. Abnormal bundling and accumulation of F-actin mediates tau-induced neuronal degeneration in vivo. Nat Cell Biol. 2007;9(2):139-148.
  21. Hong S, Beja-Glasser VF, Nfonoyim BM, Frouin A, et al. Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science. 2016;352(6286):712-716.
  22. Salminen A, Ojala J, Suuronen T, Kaarniranta K, Kauppinen A. Amyloid-β oligomers set fire to inflammasomes and induce Alzheimer's pathology. J Cell Mol Med. 2008;12(6A):2255-2262.
  23. Wang C, Fan L, Khawaja RR, Liu B, Zareini L, Bhatt DL, et al. Microglial NF-κB drives tau spreading and toxicity in a mouse model of tauopathy. Nat Commun. 2022;13(1):1969.
  24. Koenigsknecht-Talboo J, Landreth GE. Microglial phagocytosis induced by fibrillar beta-amyloid and IgGs are differentially regulated by proinflammatory cytokines. J Neurosci. 2005 Sep 7;25(36):8240-9.
  25. La Joie R, Visani AV, Baker SL, Brown JA, Bourakova V, Cha J, et al. Prospective longitudinal atrophy in Alzheimer's disease correlates with the intensity and topography of baseline tau-PET. Sci Transl Med. 2020;12(524).
  26. Huijbers W, Mormino EC, Wigman SE, Ward AM, Vannini P, Sperling RA, et al. Amyloid-β deposition in mild cognitive impairment is associated with increased hippocampal activation, atrophy, and clinical progression. Alzheimers Dement. 2015;11(9):1049-1060.
  27. Strain JF, Smith RX, Beaumont H, Roe CM, Gordon BA, et al. Loss of white matter integrity reflects tau accumulation in Alzheimer disease defined regions. Neurology. 2018 Jul 24;91(4):e313-e318.
  28. Holmes HE, Colgan N, Ismail O, Ma D, Powell NM, et al. Imaging the accumulation and suppression of tau pathology using multiparametric MRI. Neurobiol Aging. 2016 Mar;39:184-94.
  29. Sahara N, Perez PD, Lin WL, Dickson DW, Ren Y, et al. Age-related decline in white matter integrity in a mouse model of tauopathy: an in vivo diffusion tensor magnetic resonance imaging study. Neurobiol Aging. 2014 Jun;35(6):1364-74.
  30. Koch JC, Leha A, Bidner H, Cordts I, Dorst J. et al. Safety, tolerability, and efficacy of fasudil in amyotrophic lateral sclerosis (ROCK-ALS): a phase 2, randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2024 Nov;23(11):1133-1146.