Focal adhesion (FA) proteins may be critical elements in the production of dystrophic neurites in Alzheimer's disease, according to research presented in the January 15 Journal of Neuroscience.

Recent research by authors Elizabeth Grace and Jorge Busciglio of the University of Connecticut Health Center in Farmington has examined the processes by which fibrillar amyloid-beta (Aβ) can promote the development of abnormal neuronal processes (or dystrophic neurites) in vitro (Grace et al., 2002). These neurites are similar to those found associated with AD amyloid plaques-tortured processes with kinks and loops, containing filaments of hyperphosphorylated tau protein. By one school of thought, Aβ deposition and this subsequent aberrant neuronal sprouting could lead to synaptic loss and subsequent cognitive impairment in Alzheimer's (see, e.g., Saitoh et al., 1993). A corollary to this theory, the authors write, is that fibrillar Aβ may promote neuronal dystrophy and neuronal cell death by different mechanisms. Previous work by the authors suggests this notion, showing that Aβ-induced neurotoxicity and dystrophy require different Aβ concentrations and follow different time courses.

The candidate mechanism for Aβ-induced neuronal dystrophy in the current paper is the integrin receptor pathway. Previous research has shown that Aβ binds to integrins, activating the FA proteins paxillin and FA kinase (FAK) (see, e.g., Williamson et al., 2002). Because FA proteins help mediate changes in cell morphology, there is reason to hypothesize that FA signaling could have a role in Aβ-induced neuronal dystrophy.

Grace and Busciglio approached this possibility both in cultures of cortical neurons and in AD brain tissue. In whole-cell homogenates of Aβ-treated cultured neurons, they detected a dramatic increase in the level of paxillin associated with the cytoskeleton relative to untreated control cells, this despite no overall change in levels of total paxillin between controls and Aβ -treated neurons. When scrutinizing the structure of neurons exposed to Aβ, the researchers noticed aberrant neurites in areas close to Aβ deposits. Immunofluorescence indicated that these areas were also where FA proteins had clustered, leading the authors to suggest that fibrillar Aβ was promoting the clustering of FA proteins in these areas.

AD brain tissue showed strong integrin immunoreactivity, activated paxillin, and activated FAK (along with tau hyperphosphorylation) in dystrophic neurons surrounding Aβ deposits.

As shown by deletion experiments, LIM domains in the C-terminus of paxillin-areas associated with binding to b1 integrin-appear to be critical for Aβ-induced dystrophy. Point mutations in these domains demonstrated that paxillin binding to protein phosphatase PEST (PRP-PEST) is necessary for dystrophic changes. This last clue may be important, because PTP-PEST is instrumental in the dynamic modulation of FA contacts in response to extracellular cues. Might it be playing this role in response to extracellular Aβ?—Hakon Heimer

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  1. This clearly demonstrates the involvement of amyloid in potent dystrophic neurite or curly fibre formation as seen in AD. Although it remains to clarify the chemical structure of amyloid b-protein, i.e., fiber, oligomeric or beta-structure, a link between amyloid and dystophic/synaptic failure is further evidenced (cf. Selkoe 2002).

    References:

    . Alzheimer's disease is a synaptic failure. Science. 2002 Oct 25;298(5594):789-91. PubMed.

    View all comments by Hiroshi Mori
  2. Neuronal dystrophy and Aβ deposition are major pathological features of AD. Previous work has established the association of neuronal dystrophy with synaptic loss in the Alzheimer's brain (Terry et al., 1991), and cultured neurons (Grace et al., 2002). Plastic mechanisms confer to the neuron its ability to respond dynamically to environmental stimuli, and several lines of evidence suggest that misregulated mechanisms of neuronal plasticity play a major role in AD neuropathology (Cotman et al., 1998; Mesulam, 1999). Our results indicate that aberrant activation of focal adhesion (FA) proteins by fibrillar Aβ leads to dystrophic changes in neuronal cells in culture.

    We also found evidence of abnormal activation of FA proteins associated with amyloid deposits in the AD brain. Since focal adhesion signals mediate the response of cells to extracellular cues, these results suggest that, in the AD brain, alterations in the composition of the extracellular environment produced by Aβ deposition may stimulate aberrant neuronal responses. Brain regions with the highest plasticity are the most vulnerable in AD (Small, 1998), therefore, under pathological conditions, neuronal plasticity may contribute to neuronal dysfunction. In this regard, the development of therapies directed to prevent neuronal dystrophy may be useful to preserve neuronal normal structure and function as well as synaptic integrity.

    References:

    . Physical basis of cognitive alterations in Alzheimer's disease: synapse loss is the major correlate of cognitive impairment. Ann Neurol. 1991 Oct;30(4):572-80. PubMed.

    . Characterization of neuronal dystrophy induced by fibrillar amyloid beta: implications for Alzheimer's disease. Neuroscience. 2002;114(1):265-73. PubMed.

    . Cell adhesion molecules in neural plasticity and pathology: similar mechanisms, distinct organizations?. Prog Neurobiol. 1998 Aug;55(6):659-69. PubMed.

    . Neuroplasticity failure in Alzheimer's disease: bridging the gap between plaques and tangles. Neuron. 1999 Nov;24(3):521-9. PubMed.

    . The role of the amyloid protein precursor (APP) in Alzheimer's disease: does the normal function of APP explain the topography of neurodegeneration?. Neurochem Res. 1998 May;23(5):795-806. PubMed.

  3. The increased production of Aβ in Alzheimer’s disease is acknowledged to be a key pathogenic event. It is becoming apparent that Aβ itself is neurotoxic, without necessarily involving the amyloid in plaques (Small et al., 2001). For this reason, identifying proteins involved in the neurotoxic response of cells to Aβ is an important step in understanding the underlying pathogenesis of AD. Studies on the effects of Aβ on neurons have shown that it can induce a number of responses prior to cell death, including protein tyrosine phosphorylation (Luo et al., 1995). Tyrosine phosphorylation changes in signaling proteins frequently occur in response to extracellular stimuli, and can activate downstream serine/threonine kinases. It is therefore important to investigate what early changes occur in neurons after exposure to Aβ since these may be early obligatory events that ultimately lead to neuronal death. The paper by Grace and Busciglio is a highly interesting addition to the current literature on Aβ-induced neuronal responses. It examines the underlying mechanisms of neuronal dystrophy in response to Aβ, which precedes cell death.

    Central to the Aβ-induced neuronal dystrophy is the aberrant activation of focal adhesion proteins, in particular paxillin and the phosphatase PTP-PEST. Interestingly, Grace and Busciglio report that focal adhesion kinase (FAK), while involved in Aβ-induced cell death, is not involved in neuronal dystrophy, but that paxillin and PTP-PEST are involved in both neuronal dystrophy and cell death in response to Aβ. FAK has an important role in the prevention of apoptosis (Chan et al., 1999) and a central role in the transduction of cell survival signals from integrin ligands; this involves the recruitment of paxillin (Igishi et al., 1999). FAK’s role in pathological processes has previously been investigated. Prolonged exposure (48h) of neuronal cell lines to Aβ has been shown to activate FAK and increase its association with Fyn (Zhang et al., 1999). FAK activity has also been shown to be dependent on an intact cytoskeleton. Hence, the altered focal adhesion protein activity found by Grace and Busciglio in the dystrophic response of neurons to Aβ—in particular paxillin and PTP-PEST—could lead to changes in the cytoskeleton which, in turn, would affect the normally protective role of FAK.

    References:

    . Alzheimer's disease and Abeta toxicity: from top to bottom. Nat Rev Neurosci. 2001 Aug;2(8):595-8. PubMed.

    . Physiological levels of beta-amyloid increase tyrosine phosphorylation and cytosolic calcium. Brain Res. 1995 May 29;681(1-2):65-74. PubMed.

    . Suppression of ultraviolet irradiation-induced apoptosis by overexpression of focal adhesion kinase in Madin-Darby canine kidney cells. J Biol Chem. 1999 Sep 17;274(38):26901-6. PubMed.

    . Divergent signaling pathways link focal adhesion kinase to mitogen-activated protein kinase cascades. Evidence for a role of paxillin in c-Jun NH(2)-terminal kinase activation. J Biol Chem. 1999 Oct 22;274(43):30738-46. PubMed.

    . A beta peptide enhances focal adhesion kinase/Fyn association in a rat CNS nerve cell line. Neurosci Lett. 1996 Jun 28;211(3):187-90. PubMed.

References

Paper Citations

  1. . Characterization of neuronal dystrophy induced by fibrillar amyloid beta: implications for Alzheimer's disease. Neuroscience. 2002;114(1):265-73. PubMed.
  2. . Hyperactivation of signal transduction systems in Alzheimer's disease. Ann N Y Acad Sci. 1993 Sep 24;695:34-41. PubMed.
  3. . Rapid tyrosine phosphorylation of neuronal proteins including tau and focal adhesion kinase in response to amyloid-beta peptide exposure: involvement of Src family protein kinases. J Neurosci. 2002 Jan 1;22(1):10-20. PubMed.

Further Reading

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Primary Papers

  1. . Aberrant activation of focal adhesion proteins mediates fibrillar amyloid beta-induced neuronal dystrophy. J Neurosci. 2003 Jan 15;23(2):493-502. PubMed.