Cellular signaling roles of TGFβ, TNFα and βAPP in brain injury responses and Alzheimer's disease

Mark P. Mattson, Steven W. Barger, Katsutoshi Furukawa, Annadora J. Bruce, Tony Wyss-Coray, Robert J. Mark, Lennart Mucke

Research output: Contribution to journalArticlepeer-review

Abstract

β-Amyloid precursor protein (βAPP), transforming growth factor β (TGFβ), and tumor necrosis factor-α (TNFα) are remarkably pleiotropic neural cytokines/neurotrophic factors that orchestrate intricate injury-related cellular and molecular interactions. The links between these three factors include: their responses to injury; their interactive effects on astrocytes, microglia and neurons; their ability to induce cytoprotective responses in neurons; and their association with cytopathological alterations in Alzheimer's disease. Astrocytes and microglia each produce and respond to TGFβ and TNFα in characteristic ways when the brain is injured. TGFβ, TNFα and secreted forms of βAPP (sAPP) can protect neurons against excitotoxic, metabolic and oxidative insults and may thereby serve neuroprotective roles. On the other hand, under certain conditions TNFα and the fibrillogenic amyloid β-peptide (Aβ) derivative of βAPP can promote damage of neuronal and glial cells, and may play roles in neurodegenerative disorders. Studies of genetically manipulated mice in which TGFβ, TNFα or βAPP ligand or receptor levels are altered suggest important roles for each factor in cellular responses to brain injury and indicate that mediators of neural injury responses also have the potential to enhance amyloidogenesis and/or to interfere with neuroregeneration if expressed at abnormal levels or modified by strategic point mutations. Recent studies have elucidated signal transduction pathways of TGFβ (serine/threonine kinase cascades), TNFα (p55 receptor linked to a sphingomyelin-ceramide-NFκB pathway), and secreted forms of βAPP (sAPP; receptor guanylate cyclase-cGMP-cGMP-dependent kinase-K+ channel activation). Knowledge of these signaling pathways is revealing novel molecular targets on which to focus neuroprotective therapeutic strategies in disorders ranging from stroke to Alzheimer's disease.

Original languageEnglish (US)
Pages (from-to)47-61
Number of pages15
JournalBrain Research Reviews
Volume23
Issue number1-2
DOIs
StatePublished - Feb 1997
Externally publishedYes

Keywords

  • amyloid precursor protein
  • astrocyte
  • calcium
  • inflammatory cytokine
  • microglial cell
  • reactive oxygen species
  • transforming growth factor
  • tumor necrosis factor

ASJC Scopus subject areas

  • Neuroscience(all)

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