Neurodegenerative Alzheimer-like Pathology in PDAPP 717V → F Transgenic Mice

Chen, K S; Masliah, Eliezer; Grajeda, Henry; Guido, Terry; Huang, J; Khan, Karen; Motter, Ruth; Soriano, Ferdie; Games, Dora

doi:10.1007/978-3-642-60680-9_8

Cited by 19 publications

(7 citation statements)

References 42 publications

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“…Our tg mice also differs from previously described models in that most of the amyloid deposits were mature and first affected the frontal cortex, followed by the limbic system and thalamus. In contrast, in the PDAPP tg mice diffuse plaques are first observed at 6–8 mos in the hippocampus, followed by the fronto‐parietal region (Games et al, 1995, 1997; Johnson‐Wood et al, 1997). In this model, plaques containing dystrophic neurites with concomitant loss of presynaptic terminals, astrocytosis and microgliosis were observed only after 12 mos of age (Games et al, 1995, 1997; Masliah et al, 1996).…”

Section: Discussionmentioning

confidence: 97%

Early formation of mature amyloid‐β protein deposits in a mutant APP transgenic model depends on levels of Aβ_1–42

Rockenstein

Mallory

Mante

et al. 2001

J of Neuroscience Research

208

241

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The main objective of the present study was to develop an alternative singly-transgenic (tg) hAPP model where amyloid deposition will occur at an earlier age. For this purpose, we generated lines of tg mice expressing hAPP751 cDNA containing the London (V717I) and Swedish (K670M/N671L) mutations under the regulatory control of the murine (m)Thy-1 gene (mThy1-hAPP751). In the brains of the highest (line 41) and intermediate (lines 16 and 11) expressers, high levels of hAPP expression were found in neurons in layers 4-5 of the neocortex, hippocampal CA1 and olfactory bulb. As early as 3-4 months of age, line 41 mice developed mature plaques in the frontal cortex, whereas at 5-7 months plaque formation extended to the hippocampus, thalamus and olfactory region. Ultrastructural and double-immunolabeling analysis confirmed that most plaques were mature and contained dystrophic neurites immunoreactive with antibodies against APP, synaptophysin, neurofilament and tau. In addition, a decrease in the number of synaptophysin-immunoreactive terminals was most prominent in the frontal cortex of mice from line 41. Mice from line 11 developed diffuse amyloid deposits at 11 months of age, whereas mice from line 16 did not show evidence of amyloid deposition. Analysis of Abeta by ELISA showed that levels of Abeta(1-40) were higher in mice that did not show any amyloid deposits (line 16), whereas Abeta(1-42) was the predominant species in tg animals from the lines showing plaque formation (lines 41 and 11). Taken together this study indicates that early onset plaque formation depends on levels of Abeta(1-42).

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Section: Discussionmentioning

confidence: 97%

Early formation of mature amyloid‐β protein deposits in a mutant APP transgenic model depends on levels of Aβ_1–42

Rockenstein

Mallory

Mante

et al. 2001

J of Neuroscience Research

208

241

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“…48,49 It has been indirectly addressed in the transgenic mouse models of A␤ amyloid deposition, which are based on the expression of mutated amyloid precursor protein (APP). 50 -52 Although some staining for hyperphosphorylated tau has been described in nerve cell processes around A␤ deposits in transgenic mice expressing mutated APP, 52,53 no somatodendritic staining of hyperphosphorylated tau was observed in these mice. Two of these mouse lines did not exhibit nerve cell loss, 54,55 whereas a third showed a 17% reduction in the number of nerve cells in layer CA1 of the hippocampus.…”

Section: Transgenic Micementioning

confidence: 99%

The Tauopathies

Goedert

Hasegawa

1999

The American Journal of Pathology

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“…Based on the sequence and regional distribution of Aβ pathology, transgenic (Tg) animal models overexpressing wild type or mutant amyloid-β protein precursor (AβPP) have been developed that mimic some of the behavioral deficits, amyloid deposition patterns, and neurodegenerative aspects of AD [13–18]. These models support the notion that accumulation of oligomeric forms of Aβ at synaptic sites might play a role in the pathogenesis of the neurodegenerative process and memory loss in AD [19–22].…”

Section: Introductionmentioning

confidence: 99%

A Longitudinal Study of Behavioral Deficits in an AβPP Transgenic Mouse Model of Alzheimer's Disease

Havas¹,

Hutter‐Paier²,

Ubhi

et al. 2011

JAD

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Elucidating the age-dependent alterations in transgenic (Tg) mice overexpressing amyloid-β protein precursor (AβPP) is important for understanding the pathogenesis of Alzheimer’s disease (AD) and designing experimental therapies. Cross-studies have previously characterized some time-dependent behavioral and pathological alterations in AβPP Tg mice, however, a more comprehensive longitudinal study is needed to fully examine the progressive nature of behavioral deficits in these mice. In order to better understand the age- and gender-dependent progression of behavioral alterations, we performed a longitudinal study wherein Tg mice overexpressing human AβPP751 with the London (V717I) and Swedish (K670M/N671L) mutations under the regulatory control of the neuron specific murine (m)Thy-1 promoter (mThy1-hAβPP751) were behaviorally analyzed at 3 months and then re-tested at 6 and 9 months of age. The results show that there was an age-associated impairment in learning in the water maze task and habituation in the hole-board task. Motor coordination of the mThy1-hAβPP751 Tg mice was well-preserved throughout the investigated life span however, gender-specific deficits were observed in spontaneous activity and thigmotaxis. Neuropathologically, mThy1-hAβPP751 Tg mice displayed a progressive increase in the number of Aβ plaques and mean plaque size in the cortex and hippocampus from 3 to 6 and from 6 to 9 months of age. Taken together, these results indicate that the mThy1-hAβPP751 Tg mice model AD from the early onset of the disease through to later stages, allowing them to be utilized at numerous points during the timeline for drug test designs.

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Neurodegenerative Alzheimer-like Pathology in PDAPP 717V → F Transgenic Mice

Cited by 19 publications

References 42 publications

Early formation of mature amyloid‐β protein deposits in a mutant APP transgenic model depends on levels of Aβ_1–42

Early formation of mature amyloid‐β protein deposits in a mutant APP transgenic model depends on levels of Aβ_1–42

The Tauopathies

A Longitudinal Study of Behavioral Deficits in an AβPP Transgenic Mouse Model of Alzheimer's Disease

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Neurodegenerative Alzheimer-like Pathology in PDAPP 717V → F Transgenic Mice

Cited by 19 publications

References 42 publications

Early formation of mature amyloid‐β protein deposits in a mutant APP transgenic model depends on levels of Aβ1–42

Early formation of mature amyloid‐β protein deposits in a mutant APP transgenic model depends on levels of Aβ1–42

The Tauopathies

A Longitudinal Study of Behavioral Deficits in an AβPP Transgenic Mouse Model of Alzheimer's Disease

Contact Info

Product

Resources

About

Early formation of mature amyloid‐β protein deposits in a mutant APP transgenic model depends on levels of Aβ_1–42

Early formation of mature amyloid‐β protein deposits in a mutant APP transgenic model depends on levels of Aβ_1–42