Research ReportDifferent dendrite and dendritic spine alterations in basal and apical arbors in mutant human amyloid precursor protein transgenic mice
Introduction
A characteristic hallmark of Alzheimer's disease (AD) brain is the accumulation of amyloid-beta (Aβ) peptides into insoluble extracellular plaques. The Aβ peptide arises from β- and γ-secretase processing of the amyloid precursor protein (APP) (reviewed in Turner et al., 2003). The generation of Aβ during normal metabolism suggests a physiological role in normal cell function (Haass et al., 1992). However, under certain conditions, Aβ may mediate neurotoxic effects as has been observed in vitro and in vivo (reviewed in Walsh et al., 2002, McKee et al., 1998). In particular, Aβ was found to disturb synaptic transmission by depressing or modifying glutamatergic and cholinergic activity (Dutar et al., 1994, Cullen et al., 1996, Kar et al., 1996, Kasa et al., 1997, Jhamandas et al., 2001, Pettit et al., 2001, Chen et al., 2002, Raymond et al., 2003). Furthermore, soluble Aβ has been shown to affect synaptic plasticity by inhibiting the induction of long-term potentiation (Wang et al., 2002, Raymond et al., 2003), to impair initial learning and to cause dose-dependant reductions in memory retentions (Flood et al., 1991). Aggregation of Aβ into fibrils and plaque deposition initiate fatal pathological processes which are suggested to lead to the disruption of neuronal connectivity, and do correlate with the severity of dementia (Cummings et al., 1996, Knowles et al., 1999, Tomidokoro et al., 2000).
In addition to the large scale of studies focusing upon physiological and behavioral changes caused by increased soluble Aβ levels and Aβ amyloidosis (reviewed by Turner et al., 2003), morphological alterations of neurons have been addressed as well. In AD, several morphological aberrations have been observed including progressive neuritic dystrophy, ectopic sprouting and increased curvature of dendritic processes (Scheibel and Tomiyasu, 1978, Larner, 1995, Irizarry et al., 1997, Knowles et al., 1999). However, there is only little evidence about the pathogenetic factors causing changes in neuronal morphology. At least some of these changes may be due to local effects of Aβ concentration and deposition. Thus, in the close vicinity of plaques, the dendritic density is reduced (Knowles et al., 1998). Neuronal processes crossing Aβ deposits exhibit a radially changed morphology whereas segments inside are characterized by a reduced diameter and a loss of spines (Knowles et al., 1999, Le et al., 2001, Tsai et al., 2004). Moreover, amyloid deposition has been suggested to cause even neurite breakage and disruption of neuronal connections (Tsai et al., 2004).
Apart from thorough studies on focal dendritic aberrations in the microenvironment of Aβ depositions, only limited data have been presented addressing effects of elevated Aβ levels and amyloidosis on more global parameters of dendritic morphology. Therefore, the objective of the present study was to characterize alterations of apical and basal dendritic arbors of neocortical pyramidal cells in transgenic mice that developed Aβ-related pathology. We took advantage of TG2576 mice that overexpress human APP with the Swedish mutation resulting in high levels of amyloidogenic Aβ and the development of abundant cortical amyloid plaques reminiscent of AD pathology (Hsiao et al., 1996). For the assessment of morphological effects, callosal-projecting pyramidal neurons were analyzed: a population known to be most severely affected in AD (Hampel et al., 1998).
Section snippets
Results
Injection of BDA into the corpus callosum revealed a large number of retrogradely traced pyramidal neurons with Golgi-like staining in layers II, III and Vb within S1 cortex of both hemispheres (Fig. 1) that allowed ideal conditions for true 3D reconstruction of neuronal morphology (Fig. 2). However, only layer II/III neurons of the side opposite to the injection were included in the study. In Tg2576 mice, in addition to neurons, plaques stained coincidentally with the DAB reaction were well
Discussion
A number of recent studies suggest that the formation of Aβ plaques is associated with distortions in neuronal morphology (Irizarry et al., 1997, Knowles et al., 1998, Knowles et al., 1999, Le et al., 2001). Thus, within and in the close vicinity of amyloid deposits, dendritic processes become more curved and axons develop abnormally large varicosities (Le et al., 2001, Tsai et al., 2004). Alterations of neuritic morphology and trajectory may cause aberrant neuronal signaling and are thought to
Experimental procedures
The generation of mutant human APP transgenic mice has been described in detail elsewhere (Hsiao et al., 1996). Briefly, Tg2576 mice were generated by driving expression of hAPP695 containing the ‘Swedish double mutation’ (K670N, M671L) under the control of a hamster prion protein cosmid vector. In these strain, the level of Aβ40 increases fivefold and that of amyloidogenic Aβ42 actually as high as 14-fold. Tg2576 mice with an age of 9 month begin to develop abundant congophilic amyloid plaques
Acknowledgments
This study was supported by the Basic Research Foundation of Hungary (grant OTKA F 048350), the Hirnliga e.V. and by the Interdisziplinäres Zentrum für Klinische Forschung (IZKF) Leipzig at the Faculty of Medicine of the Universität Leipzig (C1). The provision of Tg2576-F1 founders by Karen Hsiao, Minnesota, USA, is gratefully acknowledged.
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