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.

Reference:
Grace EA, Busciglio J. Aberrant Activation of Focal Adhesion Proteins Mediates Fibrillar Ab-Induced Neuronal Dystrophy. J Neurosci. 2003 Jan 15;23(2).Abstract