Biology Reference
In-Depth Information
cognitive diseases such as mental retardation and prionoses. Mechanisms which may affect
dendritic spine formation and plasticity in neurodegenerative disorders will now be discussed.
A
β
-induced synaptotoxicity
In spite of their central importance to AD, the molecules responsible for spine pathology
remain unknown. Involvement of insoluble Aβ fibrils has been considered a prime suspect for
many years; however, abnormal neuropil in AD can occur in the absence of contiguous
amyloid plaques [Einstein
et al.,
1994; Lue
et al.,
1999; Coleman
et al.,
2004]. In transgenic
mouse models, synapse abnormalities as well as memory impairments correlate poorly with
plaque burden and can occur before plaque formation [Holcomb
et al.,
1999; Hsia
et al.,
1999; Larson
et al.,
1999; Mucke
et al.,
2000; Jacobsen
et al.,
2006]. Although Aβ antibodies
prevent synaptic degeneration in transgenic mice [Buttini
et al.,
2005], memory impairment is
reversed without plaque loss [Dodart
et al.,
2002; Kotilinek
et al.,
2002]. These findings
suggest that a toxin from Aβ, not present in plaques, may be the culprit behind synapse
degeneration. Indeed, AD brain [Gong
et al.,
2003; Kayed
et al.,
2003; Lacor
et al.,
2004] and
cerebrospinal fluid [Georganopoulou
et al.,
2005; Haes
et al.,
2005] contain small
neurotoxins that comprise soluble Aβ oligomers, termed Aβ-derived diffusible ligands
(ADDLs) [Lambert
et al.,
1998]. Neuronal injury triggered by ADDLs is now viewed by
many as a central feature of AD pathology [Standridge, 2006]. ADDLs are gain-of-function
ligands that target dendritic spines [Lacor
et al.,
2004] and disrupt synaptic plasticity
[Lambert
et al.,
1998; Wang
et al.,
2002].
The cellular actions of ADDLs may be of particular relevance to neutropil damage
[Klein, 2006] A recent study by Lacor
et al.
(2007) provides direct biological evidence for the
hypothesis that synaptic damage is caused by ADDLs, establishing that the latter alter spine
composition, morphology and density in highly differentiated cultures of hippocampal
neurons (a widely accepted model for studies of synapse cell biology) (Fig. 1).
ADDLs bound to neurons with specificity, attaching to presumed excitatory pyramidal
neurons but not GABAergic neurons [Lacor
et al.,
2007]. Because ADDLs block LTP
[Lambert
et al.,
1998; Wang
et al.,
2002] by binding directly to dendritic spines [Lacor
et al.,
2004] and disrupt N-methyl-D-aspartate (NMDA) receptor-mediated CREB phosphorylation
[Tong
et al.,
2001], it is not unexpected that surface glutamate receptor levels would be
altered by ADDLs [Gong
et al.,
2003]. Additionally, ADDLs induce abnormal expression of
Arc [Lacor
et al.,
2004], a spine cytoskeletal protein that influences glutamate receptor
trafficking [Mokin
et al.,
2006], and cause a major loss of surface NMDA receptors [Lacor
et
al.,
2007]. Loss of NMDA receptors has been seen in AD brain [Sze
et al.,
2001; Mishizen-
Eberz
et al.,
2004] and in a transgenic AD mouse model [Snyder
et al.,
2005], and correlates
with synaptic alterations and cognitive deficits [Terry
et al.,
1991; Sze
et al.,
1997; Counts
et
al.,
2006]. The large decrease in receptor expression reported by Lacor
et al.
(2007) occurred
prior to changes in spine density, consistent with synaptic plasticity being compromised
before onset of degeneration.
In addition to affecting NMDA receptors, ADDLs promoted a rapid decrease in
membrane expression of EphB2. These two synaptic receptors physically interact via their
extracellular domains [Dalva
et al.,
2000] and are functionally related to plasticity. NMDA
receptors play a central role in the induction of LTP [Morris and Davis, 1994], and EphB2
exerts control over NMDA-dependent LTP [Matynia
et al.,
2002]. Moreover, both receptors
