Behavioral disturbances in transgenic mice overexpressing the V717F Β-amyloid precursor protein.

Dodart, Jean-Cosme; Méziane, Hamid; Mathis, Chantal; Bales, Kelly R.; Paul, Steven M.; Ungerer, Arielle

doi:10.1037/0735-7044.113.5.982

Cited by 170 publications

(123 citation statements)

References 35 publications

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“…PDAPP mice represent a well-characterized animal model of AD-like plaque pathology with Aβ and amyloid deposition occurring in an age- and brain region-dependent fashion (14). Although these mice have behavioral deficits, they do not develop neurodegeneration or frank loss of cholinergic neurons even as they age (15)(16)(17). Here we report an Aβ-dependent disruption of hippocampal ACh release in PDAPP mice that was associated with impaired habituation learning.…”

Section: Introductionmentioning

confidence: 79%

Cholinergic dysfunction in a mouse model of Alzheimer disease is reversed by an anti-A antibody

Bales

Tzavara

Wu³

et al. 2006

Journal of Clinical Investigation

119

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Disruption of cholinergic neurotransmission contributes to the memory impairment that characterizesAlzheimer disease (AD). Since the amyloid cascade hypothesis of AD pathogenesis postulates that amyloid β (Aβ) peptide accumulation in critical brain regions also contributes to memory impairment, we assessed cholinergic function in transgenic mice where the human Aβ peptide is overexpressed. We first measured hippocampal acetylcholine (ACh) release in young, freely moving PDAPP mice, a well-characterized transgenic mouse model of AD, and found marked Aβ-dependent alterations in both basal and evoked ACh release compared with WT controls. We also found that Aβ could directly interact with the high-affinity choline transporter which may impair steady-state and on-demand ACh release. Treatment of PDAPP mice with the anti-Aβ antibody m266 rapidly and completely restored hippocampal ACh release and high-affinity choline uptake while greatly reducing impaired habituation learning that is characteristic of these mice. Thus, soluble "cholinotoxic" species of the Aβ peptide can directly impair cholinergic neurotransmission in PDAPP mice leading to memory impairment in the absence of overt neurodegeneration. Treatment with certain anti-Aβ antibodies may therefore rapidly reverse this cholinergic dysfunction and relieve memory deficits associated with early AD.

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Section: Introductionmentioning

confidence: 79%

Cholinergic dysfunction in a mouse model of Alzheimer disease is reversed by an anti-A antibody

Bales

Tzavara

Wu³

et al. 2006

Journal of Clinical Investigation

119

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“…Unlike humans with FAD, PDAPP mice do not develop NFTs or overt neuronal loss, and they have learning deficits before plaque deposition (from a few months of age, as early an age as they have been tested) (Dodart et al, 1999;Chen et al, 2000). Because these early deficits occur well before significant amounts of A␤ have accumulated or have changed into a more toxic ␤-sheet conformation, it is possible that they are caused by overexpression of human APP or any of the derivatives of APP that may influence cell function.…”

Section: Introductionmentioning

confidence: 99%

Treatment with an Amyloid-β Antibody Ameliorates Plaque Load, Learning Deficits, and Hippocampal Long-Term Potentiation in a Mouse Model of Alzheimer's Disease

Hartman¹,

Izumi²,

Bales³

et al. 2005

J. Neurosci.

138

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PDAPP transgenic mice overexpress a mutant form of human amyloid precursor protein under control of the platelet-derived growth factor promoter in CNS neurons that causes early onset, familial Alzheimer's disease in humans. These mice, on a mixed genetic background, have been shown to have substantial learning impairments from early ages, as well as an age-dependent decline in learning ability that has been hypothesized to be caused by amyloid-␤ (A␤) accumulation. The goals of this study were to determine: (1) whether PDAPP mice on a pure C57BL/6 background develop more severe age-dependent learning deficits than wild-type mice; (2) if so, whether A␤ accumulation accounts for the excessive decline in learning ability; and (3) whether the learning deficits are reversible, even after significant A␤ deposition. At 4 -6, 10 -12, or 17-19 months of age, PDAPP and littermate wild-type mice on a C57BL/6 background were tested on a 5 week water maze protocol in which the location of the escape platform changed weekly, requiring the mice to repeatedly learn new information. PDAPP mice exhibited impaired spatial learning as early as 4 months (pre-A␤ deposition), and the performance of both wild-type and PDAPP mice declined with age. However, PDAPP mice exhibited significantly greater deterioration with age. Direct evidence for the role of A␤ accumulation in the age-related worsening in PDAPP mice was provided by the observation that systemic treatment over several weeks with the anti-A␤ antibody 10D5 reduced plaque deposition, increased plasma A␤, improved hippocampal long-term potentiation, and improved behavioral performance in aged PDAPP mice with substantial A␤ burden.

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“…Spatial learning performance decreases with age (Fischer et al 1992) and in animal models with A␤ overexpression and/or A␤ plaques (Berger-Sweeney et al 1999;Dodart et al 1999;Chen et al 2000;Arendash et al 2001;Koistinaho et al 2001;Lalonde et al 2002;Kelly et al 2003). A recent study pointed out that addressing the relation between A␤ plaques and memory performance requires careful adjustment for age (Westerman et al 2002).…”

mentioning

confidence: 99%

Spatial navigation in complex and radial mazes in APP23 animals and neurotrophin signaling as a biological marker of early impairment

Hellweg¹,

Lohmann²,

Huber³

et al. 2006

Learn. Mem.

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Impairment of hippocampal function precedes frontal and parietal cortex impairment in human Alzheimer's disease (AD). Neurotrophins are critical for behavioral performance and neuronal survival in AD. We used complex and radial mazes to assess spatial orientation and learning in wild-type and B6-Tg(ThylAPP)23Sdz (APP23) animals, a transgenic mouse model of AD. We also assessed brain content of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin-3 (NT-3). Performance was alike in wild-type and APP23 animals in the radial maze. In contrast, performance in the complex maze was better in wild-type than APP23 animals. Contrary to the wild-type, hippocampal BDNF levels decreased on training in APP23 animals. Hippocampal and frontal cortex NGF levels in APP23 animals correlated with the time to solve the complex maze, but correlated inversely with escape time in wild-type animals. NT-3 levels were alike in wild-type and APP23 animals and were unchanged even after training. Both types of mazes depend on hippocampal integrity to some extent. However, according to the cognitive mapping theory of spatial learning, the complex maze because of the increased complexity of the environment most likely depends more strongly on preserved hippocampal function than the radial maze in the working memory configuration applied here. Greater impairment in complex maze performance than in radial maze performance thus resembles the predominant affliction of the loss of hippocampal function in human AD. NGF and BDNF levels on maze learning are different in wild-type and transgenic animals, indicating that biological markers of AD may be altered on challenge even though equilibrium levels are alike.

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Behavioral disturbances in transgenic mice overexpressing the V717F Β-amyloid precursor protein.

Cited by 170 publications

References 35 publications

Cholinergic dysfunction in a mouse model of Alzheimer disease is reversed by an anti-A antibody

Cholinergic dysfunction in a mouse model of Alzheimer disease is reversed by an anti-A antibody

Treatment with an Amyloid-β Antibody Ameliorates Plaque Load, Learning Deficits, and Hippocampal Long-Term Potentiation in a Mouse Model of Alzheimer's Disease

Spatial navigation in complex and radial mazes in APP23 animals and neurotrophin signaling as a biological marker of early impairment

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