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irreversibly associated by marked synapse loss [Rapoport, 1999]. Memory loss in AD may
result from synaptic dysfunction that precedes large-scale neurodegeneration, where the
synapse-to-neuron ratio is decreased by about 50% [Chapman
et al.,
1999; Chen
et al.,
2000].
This is eventually accompanied by the loss of about 10-20% of cortical neurons [Masliah,
1998].
In contrast to a continuous growth during aging, both axonal and dendritic proliferation in
AD is restricted to certain cell types and stages of the disease [Arendt
et al.,
1995a, 1998],
and is aberrant with respect to localization, morphology, cytoskeletal composition [Arendt
et
al.,
1986; McKee
et al.,
1989; Phinney
et al.,
1999], and synaptic protein expression [Geddes
et al., 1985, Ihara, 1988]. Aberrant sprouts are detectable early in AD, precede tangle
formation and occur in the absence of frank neuronal cell loss [Ihara 1988; Su
et al.,
1993]. In
AD, axon length correlates with dementia severity suggesting regressive axonal events may
be more relevant than dendritic attrition or neuronal cell loss [Anderson, 1996]. This is
consistent with degeneration of synaptic termini that then leads to secondary transneuronal
degeneration of postsynaptic dendrites [Su
et al.,
1997]. Dendritic extent in the hippocampus
normally increases with age, perhaps as a compensatory response to loss of synaptic
connections [Flood and Coleman, 1990]. This may not be sustainable, however, because
enhanced dendritic growth in early aging is followed by regression of dendritic arbors in the
latest age [Flood
et al.,
1985]. Massive somatodendritic sprouting is seen also in neocortex
and hippocampus in AD [Ihara, 1988], which may reflect unsuccessful remodeling in
response to presynaptic or axonal damage [Scott, 1993]. Disturbed neuroplastic mechanisms
might thus represent an event of primary significance, inherent to the pathobiology of AD,
rather than a response triggered by ongoing degeneration.
Dendritic spines and synaptic degeneration
As discussed above, early AD almost solely comprises severely dysfunctional memory
[Terry
et al.,
1991; Selkoe, 2002; Coleman
et al.,
2004], a specificity likely attributable to a
vulnerability of particular memory-focused synapses to degeneration [Selkoe, 2002; Scheff
and Price, 2003; Coleman
et al.,
2004]. Recent evidence suggests that synapse degeneration
begins at the level of dendritic spines, which are the loci of memory-initiating mechanisms
[Harris and Kater, 1994; Carlisle and Kennedy, 2005; Segal, 2005]. During development,
dendritic spines appear to begin as thin extensions called filopodia that then mature with an
expanded mushroom-shaped “head” linked by a neck to the dendrites [Matus, 2005]. These
protrusions from dendritic shafts exhibit dynamic changes in number, size, and shape in
response to variation in hormonal status, developmental stage, and changes in afferent input
[Fifkova, 1985; Muñoz-Cueto
et al.,
1991; Wooley and McEwen, 1992; Moser
et al.,
1994;
Murphy and Segal, 1996]. Pathological loss of spines and their associated molecules is well
documented for AD brain [Scheibel, 1983; Ferrer and Gullotta, 1990; Shim and Lubec, 2002;
Scheff and Price, 2003] and transgenic AD mouse models [Lanz
et al.,
2003; Calon
et al.,
2004; Moolman
et al.,
2004; Spires
et al.,
2005; Jacobsen
et al.,
2006], together with
significant decreases in molecules involved in spine signaling [Sze
et al.,
2001; Mishizen-
Eberz
et al.,
2004] and control of filamentous actin [Harigaya
et al.,
1996; Shim and Lubec,
2002; Counts
et al.,
2006]. Conceivably, AD dementia may be initiated before synapse
degeneration by spine aberrations. In fact, spine shape distortions are evident in other severe
