Aged APP23 mice show a delay in switching to the use of a strategy in the Barnes maze

Prut, Laëtitia; Abramowski, Dorothée; Krucker, Thomas; Levy, Coree L.; Roberts, Andrew Simon; Staufenbiel, Matthias; Wiessner, Christoph

doi:10.1016/j.bbr.2007.01.017

Cited by 33 publications

(22 citation statements)

References 22 publications

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“…Visual cliff analysis revealed that all mice had intact vision. The results (data not shown) are consistent with previous analyses of APP23 mice (9).…”

Section: Resultssupporting

confidence: 92%

Transthyretin protects Alzheimer's mice from the behavioral and biochemical effects of Aβ toxicity

Buxbaum¹,

Ye²,

Reixach³

et al. 2008

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

261

253

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Cells that have evolved to produce large quantities of secreted proteins to serve the integrated functions of complex multicellular organisms are equipped to compensate for protein misfolding. Hepatocytes and plasma cells have well developed chaperone and proteasome systems to ensure that secreted proteins transit the cell efficiently. The number of neurodegenerative disorders associated with protein misfolding suggests that neurons are particularly sensitive to the pathogenic effects of aggregates of misfolded molecules because those systems are less well developed in this lineage. Aggregates of the amyloidogenic (A␤ 1-42) peptide play a major role in the pathogenesis of Alzheimer's disease (AD), although the precise mechanism is unclear. In genetic studies examining protein-protein interactions that could constitute native mechanisms of neuroprotection in vivo, overexpression of a WT human transthyretin (TTR) transgene was ameliorative in the APP23 transgenic murine model of human AD. Targeted silencing of the endogenous TTR gene accelerated the development of the neuropathologic phenotype. Intraneuronal TTR was seen in the brains of normal humans and mice and in AD patients and APP23 mice. The APP23 brains showed colocalization of extracellular TTR with A␤ in plaques. Using surface plasmon resonance we obtained in vitro evidence of direct protein-protein interaction between TTR and A␤ aggregates. These findings suggest that TTR is protective because of its capacity to bind toxic or pretoxic A␤ aggregates in both the intracellular and extracellular environment in a chaperone-like manner. The interaction may represent a unique normal host defense mechanism, enhancement of which could be therapeutically useful.protein interaction ͉ protein misfolding ͉ amyloidosis ͉ dementia A relationship between Alzheimer's disease (AD) and transthyretin (TTR) has been hypothesized on the basis of reports of physical interaction between amyloidogenic (A␤) peptides and TTR proteins in vitro, prevention of A␤ aggregation in Caenorhabditis elegans transgenic for both mutant A␤ and TTR, increased cerebral transcription of the TTR gene in murine AD models, immunohistochemically detectable TTR in the vicinity of A␤ plaques in A␤ transgenic mice, and more aggressive histologic disease in such mice after local treatment with anti-TTR antibody (1-5). However, none of those studies demonstrated functional effects of the putative TTR-A␤ interaction. We performed genetic experiments designed to determine whether TTR has an effect on the development of the neuropathologic and behavioral phenotypes in a well characterized murine model of human AD. ResultsAPP23 mice, carrying the Swedish autosomal dominant AD mutation and displaying the neuropathologic (Congophilic plaques, gliosis, neuronal death, Congophilic angiopathy) and behavioral (defined cognitive deficits) features associated with human AD, were mated with mice overexpressing WT human TTR (hTTR) and animals in which both copies of the endogenous TTR gene had been silenced by targete...

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“…Visual cliff analysis revealed that all mice had intact vision. The results (data not shown) are consistent with previous analyses of APP23 mice (9).…”

Section: Resultssupporting

confidence: 92%

Transthyretin protects Alzheimer's mice from the behavioral and biochemical effects of Aβ toxicity

Buxbaum¹,

Ye²,

Reixach³

et al. 2008

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

261

253

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“…This is exemplified with deficits in NOR [32,[51][52][53][54][55], T-maze [50,[56][57][58][59][60] and Barnes maze [53,[61][62][63] in transgenic AD mice, which express mutant forms of amyloid precursor protein, presenilin and/or mapt (tau) genes [64,65]. It should be noticed, however, that the time course of cognitive decline is specific for each model [66].…”

Section: Discussionmentioning

confidence: 93%

Memory formation and retention are affected in adult miR-132/212 knockout mice

Hernandez-Rapp

Smith

Filali³

et al. 2015

Behavioural Brain Research

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“…These vascular changes may also be responsible for the early behavioral changes in young APP23 tg mice manifested as learning and memory deficits (50,51). Cerebral microcirculatory impairment evolving slowly and progressively over many years could be a causal factor of AD pathogenesis and may be other forms of dementia.…”

Section: Resultsmentioning

confidence: 99%

Altered morphology and 3D architecture of brain vasculature in a mouse model for Alzheimer's disease

Meyer

Ulmann-Schuler

Staufenbiel

et al. 2008

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

231

215

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Substantial evidence from epidemiological, pathological, and clinical reports suggests that vascular factors are critical in the pathogenesis of Alzheimer's disease (AD), and changes in blood flow are currently the most reliable indicators of the disease. We previously reported that older APP23 transgenic (tg) mice have significant blood flow alterations correlated with structural modifications of blood vessels. For the present study, our objective was to analyze the age-dependent morphological and architectural changes of the cerebral vasculature of APP23 tg mice. To visualize the 3D arrangement of the entire brain vasculature, we used vascular corrosion casts. Already at young ages, when typically parenchymal amyloid plaques are not yet present, APP23 tg mice had significant alterations, particularly of the microvasculature, often accompanied by small deposits attached to the vessels. In older animals, vasculature abruptly ended at amyloid plaques, resulting in holes. Often, small deposits were sitting near or at the end of truncated vessels. Between such holes, the surrounding vascular array appeared more dense and showed features typical for angiogenesis. We propose that small amyloid aggregates associated with the microvasculature lead to morphological and architectural alterations of the vasculature, resulting in altered local blood flow. The characteristic early onset of vascular alterations suggests that imaging blood flow and/or vasculature architecture could be used as a tool for early diagnosis of the disease and to monitor therapies. amyloid precursor protein ͉ cerebral blood flow ͉ scanning electron microscopy ͉ vascular corrosion casting T he typical clinical picture of Alzheimer's disease (AD) includes a progressive decline of memory function, often accompanied by other clinical signs such as agitation, aggression, sleep disturbances, and social withdrawal. Nonetheless, brain autopsy is needed to positively confirm the diagnosis (1). A high density of neuritic plaques, neurofibrillary tangles, and vascular amyloid (A␤) is a characteristic neuropathological marker of AD (2, 3). Plaques and tangles in the neuropil may affect neuronal function and also contribute to the neuronal damage; however, it is unclear whether their incidence correlates with the clinical signs and symptoms of cognitive impairment characteristic of the disease (4). Evidence suggests that cerebrovascular pathologies, such as structural alterations (5), atherosclerotic lesions (6), and impaired hemodynamic responses (7), are early features of AD (for review, see ref. 8). Reduced blood flow has been reported as one of the most consistent physiological deficits in AD (9, 10); however, it remains unclear whether the reduced cerebral blood flow is a response to neuronal damage or a factor initiating the characteristic neuropathology. In vivo studies showed the effect of A␤ on cerebral blood flow and vessel architecture in a mouse model for AD (11,12). In other models, cerebrovascular regulatory mechanisms, such as endothelium-depende...

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Aged APP23 mice show a delay in switching to the use of a strategy in the Barnes maze

Cited by 33 publications

References 22 publications

Transthyretin protects Alzheimer's mice from the behavioral and biochemical effects of Aβ toxicity

Transthyretin protects Alzheimer's mice from the behavioral and biochemical effects of Aβ toxicity

Memory formation and retention are affected in adult miR-132/212 knockout mice

Altered morphology and 3D architecture of brain vasculature in a mouse model for Alzheimer's disease

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