Reversal of Alzheimer's-like pathology and behavior in human APP transgenic mice by mutation of Asp664

Galván, Verónica; Gorostiza, Olivia; Banwait, Surita; Ataie, Marina; Logvinova, Anna; Sitaraman, Sandhya; Carlson, Elaine J.; Sagi, Sarah A.; Chevallier, Nathalie; Jin, Kunlin; Greenberg, David A.; Bredesen, Dale E.

doi:10.1073/pnas.0509695103

Cited by 214 publications

(339 citation statements)

References 32 publications

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“…We also see significant changes in the cerebellum, which shows no thioflavin-positive amyloid deposition. While plaque-associated metabolic decline in one ROI could be expected to drive changes throughout an interconnected network, there is also increasing support for the role of soluble and/or intracellular APP products in the disruption of cellular processes in AD (Gouras et al, 2005 for a review) as well as in transgenic animal models (Galvan et al, 2006). …”

Section: Discussionmentioning

confidence: 99%

Age- and transgene-related changes in regional cerebral metabolism in PSAPP mice

2006

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In parallel to imaging studies in humans with Alzheimer's disease (AD), we have mapped brain metabolic activity in transgenic mouse models of AD. Our aim in both is to provide new surrogate markers of progression to help clarify disease mechanisms and rapidly screen candidate therapeutics. Since previous findings of preferential reductions in posterior cingulate glucose metabolism may have been confounded by morphological abnormalities in previously studied "PDAPP" transgenic mice, we first assessed hippocampal and callosal anatomy in PSAPP (PS1×APP) mice, another transgenic mouse model of AD, and found no major abnormalities. We then used fluorodeoxyglucose (FDG) autoradiography in older and younger PSAPP and wildtype mice to assess the functional state of 56 regions-of-interest across group, age and increasing amyloid load. Reductions in FDG uptake in aged transgenic mice, with significant interactions between group and age, were found in retrosplenial cingulate gyrus, found to be metabolically affected in persons affected by or at risk for AD, and in brain regions known to participate with retrosplenial cingulate in networks contributing to spatial learning deficits found in these animals. Like patients with AD, PSAPP mice have agerelated metabolic reductions in posterior cingulate cortex, a finding that does not appear to be related to morphological abnormalities. If longitudinal studies support these progressive and preferential reductions in retrosplenial metabolism in PSAPP mice, these reductions could provide an indicator of disease progression, help bridge the gap between human and animal studies of AD, and aid in clarification of disease mechanisms and screening of promising treatments.

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Section: Discussionmentioning

confidence: 99%

Age- and transgene-related changes in regional cerebral metabolism in PSAPP mice

2006

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“…However, recent studies suggest a critical role for cell-death mediators in neurodegenerative diseases, even before the reduction in neuronal number. For example, in a transgenic mouse model of AD that features senile plaques, synapse and memory loss, but little or no neuronal loss, mutation of the caspase cleavage site at Asp 664 in the amyloid precursor protein (APP) completely suppressed synapse loss, dentate gyral atrophy, astrogliosis and memory loss, even though senile plaque number and amyloid-β concentrations were unaffected 46 . In an analogous study with an HD-transgenic mouse model, mutation of the caspase-6 site (but not the caspase-3 sites) in polyglutamine-expanded huntingtin prevented both the neurodegeneration and motor abnormalities characteristic of Huntington's disease 47 .…”

Section: Triggering Cell Death In Neurodegenerationmentioning

confidence: 99%

Cell death in the nervous system

Bredesen

Rao

Mehlen

2006

Nature

Self Cite

575

418

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Neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease trigger neuronal cell death through endogenous suicide pathways. Surprisingly, although the cell death itself may occur relatively late in the course of the degenerative process, the mediators of the underlying celldeath pathways have shown promise as potential therapeutic targets.Thank Heaven! The crisis -the danger, is past, and the lingering illness, is over at last -and the fever called "Living" is conquered at last. from For Annie, by Edgar Allan Poe Programmed cell death (PCD) has a critical role in the development of the nervous system, and both anti-PCD and pro-PCD modulators feature prominently in the establishment of neural architecture. It has been 100 years since the first description of developmental neuronal-cell death 1 , and more than 50 years since Levi-Montalcini showed that such physiological cell death is inhibited by soluble factors such as nerve growth factor 2 . Dysregulation of cell-death programmes features in developmental and neoplastic disorders of the nervous system, and there is increasing evidence to suggest that such dysregulation may also occur in neurodegenerative, infectious, traumatic, ischaemic, metabolic and demyelinating disorders.In 1964, Lockshin and his colleagues introduced the term programmed cell death to describe the apparently predetermined pattern by which specific cells die during insect development 3 . In 1966, it was shown that this process requires protein synthesis, at least in some cases 2 , indicating that it is the result of an active cellular suicide process. Then, in 1972, John Kerr and his colleagues coined the term apoptosis to describe a morphologically relatively uniform set of cell deaths seen in many different situations, from development to insult response to cell turnover 4 .Although PCD has often been equated with apoptosis, non-apoptotic forms also exist [5][6][7][8][9] , and neurodegenerative conditions such as Huntington's disease, amyotrophic lateral sclerosis (ALS) and ischaemia show cell deaths that do not fulfil the criteria for apoptosis 7 .Classical developmental studies support the view that at least three different forms of PCD are distinguishable (Table 1) 3,5,8 ; and type III, also known as cytoplasmic 5,6,8,10 . These occur reproducibly in specific nuclei and with specific frequencies, at particular times of nervous-system development. But these cell-death pathways may also be activated by various insults, such as DNA damage or the accumulation of misfolded proteins.Neurodegenerative diseases are associated with a number of insults that may trigger PCD: misfolded proteins, reactive oxygen and nitrogen species, mitochondrial-complex inhibition, calcium entry, excitotoxicity, trophic-factor withdrawal, and death-receptor activation to name a few. In some cases, however, deaths occur that do not fit neatly into any of the three classes of PCD, and these more controversial forms of death are also discussed below.Temporal studies of neurodegenerative m...

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“…These findings are paralleled by results that show the aberrant cleavage of caspase-6 substrates in brain tissue from patients suffering from HD or AD [90][91][92] . Interestingly, the disease-causing proteins mHtt, Tau and APP are substrates for caspase-6, and the abrogation of mHtt or APP cleavage in mouse models is protective and leads to a dramatic improvement of the disease phenotype 93,94 .…”

Section: Preventing Caspase-6 Cleavage Is Beneficial In Ad and Hdmentioning

confidence: 99%

“…Reduced BDNF levels 39,40 Increasing BDNF & NGF levels is beneficial in disease models [51][52][53][54] Increased p75 NTR levels and signalling 75,172 Decreased Trk receptor levels and signalling 75,172 Increased Gsk3ß activity 66,173 Altered ERK activity 174 Reduced velocity and efficiency of axonal transport of BDNF 65,66 Apoptotic pathways Increased caspase-6 activity 89,90 Caspase-6 cleavage of disease proteins [89][90][91][92] Preventing caspase cleavage of disease proteins is beneficial in mouse models 93,94 Posttranslational modifications Palmitoylation of disease proteins is linked to aggregate formation 118,119 Phosphorylation of disease proteins reduces their cleavage by caspases 105,106 HDAC inhibition is beneficial in disease models 69,126,127 Protein aggregation and clearance mechanisms Misfolding and aggregation of disease proteins 128 UPS impairment 144,145 Impaired autophagy 161 Upregulation of autophagy is beneficial in disease models 153,155,156,158,162,163,165,167,<...>…”

Section: Supplementary Materialsmentioning

confidence: 99%

Convergent pathogenic pathways in Alzheimer's and Huntington's diseases: shared targets for drug development

Ehrnhoefer

Wong

Hayden

2011

Nat Rev Drug Discov

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Neurodegenerative diseases exemplified by Alzheimer's and Huntington disease are characterized by the progressive neuropsychiatric dysfunction and loss of specific neuronal subtypes. Even though there are differences in the exact sites of pathology and clinical profiles only partially overlap, considerable similarities in disease mechanisms and pathogenic pathways can be observed. These shared mechanisms raise the possibility of common therapeutic targets for drug development. Huntington disease with a monogenic cause and the possibility to accurately identify pre-manifest mutation carriers could be exploited as a 'model' for Alzheimer's disease to test the efficacy of therapeutic interventions targeting shared pathogenic pathways.

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Reversal of Alzheimer's-like pathology and behavior in human APP transgenic mice by mutation of Asp664

Abstract: CorrectionsAGRICULTURAL SCIENCES. For the article ''Characterization of capsaicin synthase and identification of its gene (csy1) for pungency factor capsaicin in pepper (Capsicum sp.),'' by B. C. Narasimha

Cited by 214 publications

References 32 publications

Age- and transgene-related changes in regional cerebral metabolism in PSAPP mice

Age- and transgene-related changes in regional cerebral metabolism in PSAPP mice

Cell death in the nervous system

Convergent pathogenic pathways in Alzheimer's and Huntington's diseases: shared targets for drug development

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