Progressive and gender-dependent cognitive impairment in the APPSW transgenic mouse model for Alzheimer’s disease

King, David L; Arendash, Gary W.; Crawford, Fiona; Sterk, Troy; Menendez, Julian; Mullan, Michael

doi:10.1016/s0166-4328(99)00037-6

Cited by 198 publications

(155 citation statements)

References 28 publications

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“…The increased transfer latency in the passive avoidance task in 3xTgAD mice is a result expected from impaired memory for the punishment, but could also result from increased anxiety. In contrast to our results with 3xTgAD mice, APP mutant mice (King et al, 1999;Lim et al, 2001) exhibited increased open field activity. This difference may be the result of differential Aβ pathology in the two different models, or to the tau pathology present in the 3xTgAD mice, but lacking in the APP mutant mice.…”

Section: Discussioncontrasting

confidence: 99%

Prophylactic treatment with paroxetine ameliorates behavioral deficits and retards the development of amyloid and tau pathologies in 3xTgAD mice

Nelson

Guo

Halagappa

et al. 2007

Experimental Neurology

163

133

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A history of depression is a risk factor for Alzheimer's disease (AD), suggesting the possibility that antidepressants administered prophylactically might retard the disease process and preserve cognitive function. Here we report that pre-symptomatic treatment with the antidepressant paroxetine attenuates the disease process and improves cognitive performance in the 3xTgAD mouse model of AD. Five month-old male and female 3xTgAD and non-transgenic mice were administered either paroxetine or saline daily for 5 months. Open-field activity was tested in 7 month-old mice and performance in passive avoidance and Morris swim tasks were evaluated at 10 months. 3xTgAD mice exhibited reduced exploratory activity, increased transfer latency in the passive avoidance test and impaired performance in the Morris spatial navigation task compared to nontransgenic control mice. Paroxetine treatment ameliorated the spatial navigation deficit in 3xTgAD male and female mice, without affecting swim speed or distance traveled, suggesting a preservation of cognitive function. Levels of amyloid beta-peptide (Aβ) and numbers of Aβ immunoreactive neurons were significantly reduced in the hippocampus of male and female paroxetine-treated 3xTgAD mice compared to saline-treated 3xTgAD mice. Female 3xTgAD mice exhibited significantly less tau pathology in the hippocampus and amygdala compared to male 3xTgAD mice, and paroxetine lessened tau pathology in male 3xTgAD mice. The ability of a safe and effective antidepressant to suppress neuropathological changes and improve cognitive performance in a mouse model, suggests that such drugs administered prophylactically might retard the development of AD in humans.

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Section: Discussioncontrasting

confidence: 99%

Prophylactic treatment with paroxetine ameliorates behavioral deficits and retards the development of amyloid and tau pathologies in 3xTgAD mice

Nelson

Guo

Halagappa

et al. 2007

Experimental Neurology

163

133

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“…This hypothesis seems reasonable because increased soluble A␤ has been demonstrated to exhibit neurotoxicity (33,42,54), which is likely to induce early-onset neuropathology reminiscent of AD (23,24,26,(29)(30)(31)(32)42). The contribution of soluble A␤ to observed dendritic pathology was further supported by the fact that diffuse deposits of A␤ were undetectable with 3D6 immunohistochemistry in the DG of 90-d Tg mice (J. F. Reilly, personal communication; see ref.…”

Section: Possible Mechanisms Underlying Dendritic Atrophy Of Gcs Of Pmentioning

confidence: 93%

“…Moreover, the fact that the impact of soluble A␤ induces dendritic alterations of the GCs in the absence of A␤ deposits is likely to play a major role in cognitive deficits of 90-d Tg mice (10,24). Although the mechanisms of APP overexpression that induce early-onset dendritic pathology require further investigation, e.g., the intracellular accumulation and͞or aberrant proteolytic processing of APP (55)(56)(57)(58)(59), the present study has confirmed the presence of A␤ toxicity before the deposition of plaques and has specifically localized it to the dorsal blade SGCs of the posterior portion of the DG, providing a morphological correlate to the pathological deficits observed in young Tg mice (22)(23)(24)(25)(26)(27)(28)35). Future studies are necessary to investigate the A-P levels of soluble A␤ within the subfields of the DG, which can then be correlated to the selective dendritic pathology of GCs reported in the current study.…”

Section: Possible Mechanisms Underlying Dendritic Atrophy Of Gcs Of Pmentioning

confidence: 99%

“…The findings from these mouse models support the conclusion that, whereas AD is a progressive human disease culminating in dementia, pathological changes and more subtle functional deficits may appear well in advance of obvious memory loss and cognitive impairment. Given that soluble forms of A␤ have been suggested to lead to neuropathological changes well in advance of its deposition as plaques (23,24,26,(30)(31)(32)(33), the early detection of any pathological conditions induced by mutant APP overexpression could provide a basis for evaluation of potential early therapeutic intervention (3,5,34).…”

mentioning

confidence: 99%

“…One such Tg mouse line, PDAPP mice, overexpresses human APP with the 717V3F Indian mutation, and exhibits extensive A␤ deposition in an age-and brain region-specific manner, analogous to that seen in human AD patients, in particular, in the hippocampus (3,(6)(7)(8)16). Recent evidence indicates that PDAPP mice exhibit early behavioral (10,(22)(23)(24), biochemical (25,26), electrophysiological (27,28), and morphological (29) changes in the hippocampus before the onset of amyloid deposition. The findings from these mouse models support the conclusion that, whereas AD is a progressive human disease culminating in dementia, pathological changes and more subtle functional deficits may appear well in advance of obvious memory loss and cognitive impairment.…”

mentioning

confidence: 99%

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Selective vulnerability of dentate granule cells prior to amyloid deposition in PDAPP mice: Digital morphometric analyses

Chawla

Games

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

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Increasing evidence from mouse models of Alzheimer's disease shows that overexpression of a mutant form of the amyloid precursor protein (APP) and its product, ␤-amyloid peptide, initiate pathological changes before amyloid deposition. To evaluate the cytological basis for one of these early changes, namely reduced volume of the dentate gyrus (DG), we have used high-throughput diOlistic cell loading and 3D neuronal reconstruction to investigate potential dendritic pathology of granule cells (GCs) in 90-day-old PDAPP mice. Labeled GCs from fixed hippocampal slices were selected randomly and imaged digitally by using confocal laserscanning microscopy. The dendritic complexity of GCs was quantified according to subordinate morphological parameters, including soma position within the granule cell layer (superficial versus deep) and topographic location within the DG (dorsal versus ventral blade) along the anterior-posterior hippocampal axis. Initial analysis, which included all sampled GC types, revealed a 12% reduction of total dendritic length in PDAPP mice compared with littermate controls. Further analysis, performed with refined subgroups, found that superficially located GCs in the dorsal blade were profoundly altered, exhibiting a 23% loss in total dendritic length, whereas neurons in the ventral blade were unaffected. Superficial GCs were particularly vulnerable (a 32% reduction) in the posterior region of the DG. Furthermore, the dendritic reductions of this select group were uniformly localized within middleto-outer portions of the dentate molecular layer. We conclude that substantial dendritic pathology is evident in 90-day-old PDAPP mice for a spatially defined subset of GCs well before amyloid accumulation occurs.T he classical neuropathological hallmarks of Alzheimer's disease (AD) include the presence of neurofibrillary tangles within neurons and extracellular cerebrovascular, diffuse, and neuritic plaques (1). The key molecular constituent of the plaque is ␤-amyloid (A␤), a 39-to 43-amino acid amyloidogenic peptide, which is a product of the proteolytic processing of the amyloid precursor protein (APP) (2). It has been shown that familial APP mutations may facilitate AD-like neuropathological changes by accelerating aberrant APP proteolytic processing. This hypothesis has been reinforced by evidence from transgenic (Tg) mouse models of AD in which overexpression of mutant APP results in amyloid deposition (3-10). Neuritic dystrophy associated with the deposits of A␤ in AD brains is evidenced by progressive dendritic dystrophy within the hippocampal complex (11-17). Although the assumption has been that A␤ deposition leads to neuritic dystrophy that would impair hippocampal function (18,19), the causal links between the deposition and pathology have been largely inferential, with minimal data available on the time course of these events.Tg mouse models have provided a unique opportunity to characterize A␤-induced neuropathology, including the nature and time of onset of the physiological and morpholog...

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Progressive age‐related development of Alzheimer‐like pathology in APP/PS1 mice

Trinchese

Liu

Battaglia

et al. 2004

Annals of Neurology

325

217

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Increasing evidence points to synaptic plasticity impairment as one of the first events in Alzheimer's disease (AD). However, studies on synaptic dysfunction in different transgenic AD models that overexpress familial AD mutant forms of amyloid precursor protein (APP) and/or presenilin (PS) have provided conflicting results. Both long-term potentiation (LTP) and basal synaptic transmission (BST) have been found to be both unchanged and altered in different models and under differing experimental conditions. Because of their more robust amyloid-beta (Abeta) deposition, double transgenic mice currently are used by several laboratories as an AD model. Here, we report that mice overexpressing APP (K670N:M671L) together with PS1 (M146L) have abnormal LTP as early as 3 months of age. Interestingly, reduced LTP paralleled plaque appearance and increased Abeta levels and abnormal short-term memory (working memory). BST and long-term memory (reference memory) are impaired only later (approximately 6 months) as amyloid burden increases. Abeta pathology across different ages did not correlate with synaptic and cognitive deficits, suggesting that Abeta levels are not a marker of memory decline. In contrast, progression of LTP impairment correlated with the deterioration of working memory, suggesting that percentage of potentiation might be an indicator of the cognitive decline and disease progression in the APP/PS1 mice.

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Progressive and gender-dependent cognitive impairment in the APPSW transgenic mouse model for Alzheimer’s disease

Cited by 198 publications

References 28 publications

Prophylactic treatment with paroxetine ameliorates behavioral deficits and retards the development of amyloid and tau pathologies in 3xTgAD mice

Prophylactic treatment with paroxetine ameliorates behavioral deficits and retards the development of amyloid and tau pathologies in 3xTgAD mice

Selective vulnerability of dentate granule cells prior to amyloid deposition in PDAPP mice: Digital morphometric analyses

Progressive age‐related development of Alzheimer‐like pathology in APP/PS1 mice

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