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

Öz

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.

Anahtar Kelimeler

• Alzheimers disease
• Amyloid beta
• tau Proteins
• Microglia
• Neuroinflammation

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

Öz

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.

Anahtar Kelimeler

• Alzheimer hastalığı
• Amiloid beta
• Tau proteini
• Aktin
• Mikroglia
• Nöroinflamasyon

Destekleyen Kurum

Yazarlar bu çalışma için finansal destek almadıklarını beyan etmişlerdir.

Etik Beyan

Bu çalışma, daha önce yayımlanmış literatürün derlenmesine dayanan bir derleme makalesidir. Birincil veri toplama, insan katılımcı veya hayvan deneyi içermediğinden etik kurul onayı gerekmemiştir. Çalışmanın tüm aşamalarında araştırma ve yayın etiği ilkelerine uyulmuştur.

Teşekkür

Eskişehir Osmangazi Üniversitesi Tıp Fakültesi Eğitim Koordinasyon Birimi tarafından düzenlenen Öğrenci Sosyal Sorumluluk Projeleri etkinliğin için teşekkürlerimizi sunarız.

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