Grace EA, Busciglio J.
Aberrant activation of focal adhesion proteins mediates fibrillar amyloid beta-induced neuronal dystrophy.
J Neurosci. 2003 Jan 15;23(2):493-502.
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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.
Terry RD, Masliah E, Salmon DP, Butters N, DeTeresa R, Hill R, Hansen LA, Katzman R.
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.
Grace EA, Rabiner CA, Busciglio J.
Characterization of neuronal dystrophy induced by fibrillar amyloid beta: implications for Alzheimer's disease.
Cotman CW, Hailer NP, Pfister KK, Soltesz I, Schachner M.
Cell adhesion molecules in neural plasticity and pathology: similar mechanisms, distinct organizations?.
Prog Neurobiol. 1998 Aug;55(6):659-69.
Neuroplasticity failure in Alzheimer's disease: bridging the gap between plaques and tangles.
Neuron. 1999 Nov;24(3):521-9.
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.
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.
Small DH, Mok SS, Bornstein JC.
Alzheimer's disease and Abeta toxicity: from top to bottom.
Nat Rev Neurosci. 2001 Aug;2(8):595-8.
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J Biol Chem. 1999 Sep 17;274(38):26901-6.
Igishi T, Fukuhara S, Patel V, Katz BZ, Yamada KM, Gutkind JS.
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.
Zhang C, Qiu HE, Krafft GA, Klein WL.
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.
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).
Alzheimer's disease is a synaptic failure.
Science. 2002 Oct 25;298(5594):789-91.
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