Degenerative and protective signaling mechanisms in the neurofibrillary pathology of AD

Mark P. Mattson

Research output: Contribution to journalArticlepeer-review

41 Scopus citations


Attention has focussed on the molecular alterations in neurofibrillary tangles (NFT) in Alzheimer's disease (AD) with the presumption that the events leading to the alterations are involved in the neurodegenerative mechanism. Here I propose that some of the manifestations of NFT result from activation of neuroprotective signaling cascades such as those induced by neurotrophic factors. Increasing data implicate free radicals and calcium in the mechanism of neuronal injury (including cytoskeletal pathology) and death in AD. Increased accumulation of β-amyloid peptide (Aβ), reduced energy availability, and increased oxidative processes are among the age-associated changes in AD that appear to be upstream to increases in cellular free radicals and calcium. Neurotrophic factors influence the expression of gene products known to stabilize calcium homeostasis, suppress free radical accumulation, and protect neurons against AD-relevant insults. The events leading to the cytoskeletal alterations in NFT are not clear although some of the alterations can be induced by excitotoxic and metabolic insults. On the other hand, kinases activated by neurotrophic factors may contribute to tau hyperphosphorylation during brain development and in AD. Activities in both degenerative and protective signaling pathways are subject to modification by aging, and by genetic and environmental factors, suggesting that the multiple cytoskeletal alterations in NFT probably result from concurrent activation of both neurodegenerative and neuroprotective cascades.

Original languageEnglish (US)
Pages (from-to)447-457
Number of pages11
JournalNeurobiology of Aging
Issue number3
StatePublished - 1995
Externally publishedYes


  • Amyloid
  • Antioxidant enzymes
  • Calcium
  • Excitatory amino acid
  • Free radical
  • Glutamate Ion-motive ATPase
  • Microtubule-associated protein
  • Neurotrophic factors
  • Tau
  • Tyrosine kinase

ASJC Scopus subject areas

  • Aging
  • Developmental Biology
  • Geriatrics and Gerontology
  • Clinical Neurology
  • Neuroscience(all)
  • Biological Psychiatry
  • Developmental Neuroscience
  • Neurology
  • Psychology(all)


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