TGF-β1 signalling in Alzheimer’s pathology and cytoskeletal reorganization: a specialized Tau perspective

Abstract

Microtubule-associated protein, Tau has been implicated in Alzheimer's disease for its detachment from microtubules and formation of insoluble intracellular aggregates within the neurons. Recent findings have suggested the expulsion of Tau seeds in the extracellular domain and their prion-like propagation between neurons. Transforming Growth Factor-β1 (TGF-β1) is a ubiquitously occurring cytokine reported to carry out immunomodulation and neuroprotection in the brain. TGF-β-mediated regulation occurs at the level of neuronal survival and differentiation, glial activation (astrocyte and microglia), amyloid production–distribution–clearance and neurofibrillary tangle formation, all of which contributes to Alzheimer's pathophysiology. Its role in the reorganization of cytoskeletal architecture and remodelling of extracellular matrix to facilitate cellular migration has been well-documented. Microglia are the resident immune sentinels of the brain responsible for surveying the local microenvironment, migrating towards the beacon of pertinent damage and phagocytosing the cellular debris or patho-protein deposits at the site of insult. Channelizing microglia to target extracellular Tau could be a good strategy to combat the prion-like transmission and seeding problem in Alzheimer's disease. The current review focuses on reaffirming the role of TGF-β1 signalling in Alzheimer’s pathology and cytoskeletal reorganization and considers utilizing the approach of TGF-β-triggered microglia-mediated targeting of extracellular patho-protein, Tau, as a possible potential strategy to combat Alzheimer's disease.

Transcriptomic analysis reveals sex-specific patterns in the hippocampus in Alzheimer’s disease

“…The TGF-beta signaling pathway was found to be downregulated in F-AD vs. F-controls in the GSE48350 dataset. TGF-beta, including isoforms TGF-β1, -2, and -3 are pleiotropic cytokines with neuroprotective, and immunoregulation functions ( 36 , 37 ). The TGF-β type II receptor (TβRII) is mainly expressed by neurons, and its levels are reduced in human AD brain, correlating with pathological hallmarks of the disease ( 37 ).…”

“…TGF-beta, including isoforms TGF-β1, -2, and -3 are pleiotropic cytokines with neuroprotective, and immunoregulation functions ( 36 , 37 ). The TGF-β type II receptor (TβRII) is mainly expressed by neurons, and its levels are reduced in human AD brain, correlating with pathological hallmarks of the disease ( 37 ). Numerous studies suggest that a decline in TGF-β1 signaling is closely associated with increased deposition of Aβ plaques and NFTs in AD.…”

Identification of prognostic cancer-associated fibroblast markers in luminal breast cancer using weighted gene co-expression network analysis

“…Furthermore, CAFs secrete fibronectin, which activates integrin receptors on cancer cells, triggering signaling pathways that enhance cancer cell proliferation, survival, and migration ( 56 , 57 ). In addition, CAFs regulate the actin cytoskeleton of cancer cells, facilitating their ability to invade and migrate, by secreting growth factors such as TGF-β that promote the formation of stress fibers essential for cell migration and invasion ( 58 , 59 ).…”

Biomarkers in Alzheimer’s Disease: Are Olfactory Neuronal Precursors Useful for Antemortem Biomarker Research?

“…However, Aβ species may induce chronic neuroinflammation by stimulating the microglia to release pro-inflammatory cytokines and interfering with the synthesis of anti-inflammatory cytokines. Tumor growth factor β1 (TGF-β1) and tumor necrosis factoralpha (TNF-α) are cytokines that exert opposite effects on microglia: while TGF-β1 has an anti-inflammatory effect [59], under pathological conditions like AD, TNF-α is chronically released by activated microglia, neurons, and astrocytes, and, in a vicious cycle, increased levels of extracellular Aβ stimulate its release [60]. TNF-α can stimulate γ-secretase activity, resulting in increased synthesis of Aβ peptides and a further increase in TNF-α release [61].…”