Alzheimer-type neuropathology in transgenic mice overexpressing V717F β-amyloid precursor protein

  title={Alzheimer-type neuropathology in transgenic mice overexpressing V717F $\beta$-amyloid precursor protein},
  author={D. Games and David John Adams and Ree Alessandrini and Robin M. Barbour and Patricia Borthelette and Catherine E Blackwell and Tony Carr and James Clemens and Thomas Donaldson and Frances P. Gillespie and Terry Guido and S S Hagopian and Kelly Johnson-wood and Karen Khan and Mike Lee and Paul J. Leibowitz and Ivan M. Lieberburg and Sheila P. Little and Eliezer Masliah and Lisa McConlogue and Mart{\'i}n Montoya-Zavala and Lennart Mucke and Lisa Paganini and Elizabeth Pash Penniman and Mike Power and Dale B. Schenk and Peter Seubert and B W Snyder and Ferdie Soriano and Hua Tan and James A. Vitale and Samuel C. Wadsworth and Benjamin Wolozin and Jun Zhao},
ALZHEIMER'S disease (AD) is the most common cause of progressive intellectual failure in aged humans. AD brains contain numerous amyloid plaques surrounded by dystrophic neurites, and show profound synaptic loss, neurofibrillary tangle formation and gliosis. The amyloid plaques are composed of amyloid β-peptide (Aβ), a 40–42-amino-acid fragment of the β-amyloid precursor protein (APP)1. A primary pathogenic role for APP/Aβ is sug-gested by missense mutations in APP that are tightly linked to… 

Two amyloid precursor protein transgenic mouse models with Alzheimer disease-like pathology.

These mice resemble major features of AD pathology and suggest a central role of A beta in the pathogenesis of the disease.

Mechanism of Neuronal Death in Alzheimer’s Disease

The idea that a subset of amyloid deposits in hAPP transgenic mice is focally toxic to neurons is developed, which would suggest that the primary toxic effects in these mice appear to be mediated by amyloids deposition.

Immunization with amyloid-β attenuates Alzheimer-disease-like pathology in the PDAPP mouse

It is reported that immunization of the young animals essentially prevented the development of β-amyloid-plaque formation, neuritic dystrophy and astrogliosis, and treatment of the older animals markedly reduced the extent and progression of these AD-like neuropathologies.

β-Amyloid precursor protein transgenic mice that harbor diffuse Aβ deposits but do not form plaques show increased ischemic vulnerability: Role of inflammation

Findings elucidate molecular mechanisms of neuronal injury in AD and suggest that antiinflammatory compounds preventing activation of p38 MAPK in microglia may reduce neuronal vulnerability in AD.

Mouse models of Alzheimer's disease: The long and filamentous road

Tangle-like pathologies are observed in mice expressing FTPD-17 mutant forms of tau, but florid tau pathologies based upon the wild type tau isoforms present in AD have proven more elusive.

β-Amyloid Plaques in a Model for Sporadic Alzheimer's Disease Based on Transgenic Anti-Nerve Growth Factor Antibodies

The chronic deprivation of NGF leads to the formation and deposition of Abeta in AD11 mice, suggesting a direct link between NGF signaling and abnormal processing of amyloid precursor protein.

Genetics of β-Amyloid Precursor Protein in Alzheimer's Disease.

  • J. TcwA. Goate
  • Biology
    Cold Spring Harbor perspectives in medicine
  • 2017
Alzheimer's disease (AD) is characterized neuropathologically by neuronal cell loss, extracellular neuritic plaques composed of β-amyloid (Aβ), and intracellular neurofibrillary tangles composed of

Genetic background regulates β-amyloid precursor protein processing and β-amyloid deposition in the mouse

It is demonstrated that APP processing, Ab metabolism and Ab deposition are regulated by genetic background and that analysis of these phenotypes in mice should provide new insights into the factors that regulate AD pathogenesis.

Plaque-independent disruption of neural circuits in Alzheimer's disease mouse models.

  • A. HsiaE. Masliah L. Mucke
  • Biology
    Proceedings of the National Academy of Sciences of the United States of America
  • 1999
It is shown that overexpression of FAD(717V-->F)-mutant human APP in neurons of transgenic mice decreases the density of presynaptic terminals and neurons well before these mice develop amyloid plaques, suggesting a neurotoxic effect of Abeta that is independent of plaque formation.



Transgenic mouse brain histopathology resembles early Alzheimer's disease

It is shown that the murine brain is capable of reproducing several typical features of Alzheimer histopathology, including dense Aβ immunoreactivity which co‐localizes with gliosis and with Alz50‐immunoreactive structures resembling swollen boutons of dystrophic neurites.

Formation of β-amyloid protein deposits in brains of transgenic mice

The results suggest that one mechanism of β-amyloid formation may involve a disruption of the normal ratio of neuronal β-APP isoform expression and support a direct relationship between increased expression of Kunitz inhibitor-bearing β- APP isoforms and β-AMyloid deposition.

Reversible in vitro growth of Alzheimer disease beta-amyloid plaques by deposition of labeled amyloid peptide.

The use of radioiodinated beta A4 provides an in vitro system for the quantitative evaluation of agents or conditions that may inhibit or enhance the growth or dissolution of AD plaques and an extremely sensitive method for visualizing various types of amyloid deposits.

A mutation in the amyloid precursor protein associated with hereditary Alzheimer's disease.

Direct sequencing of DNA from a family with autopsy-proven Alzheimer's disease revealed a single amino acid substitution (Phe for Val) in the transmembrane domain of the amyloid precursor protein, which may be the inherited factor causing both amyloids fibril formation and dementia.

Defined neurofilament, tau, and beta-amyloid precursor protein epitopes distinguish Alzheimer from non-Alzheimer senile plaques.

Differences between the complement of beta-APP, tau, and NF protein epitopes in AD versus non-AD brains implicate a defect involving one or more steps in the posttranslational modification, degradation, or elimination of these proteins in AD brains, and this may account for the massive numbers of SPs that characterize AD.

Expression of the human beta-amyloid precursor protein gene from a yeast artificial chromosome in transgenic mice.

  • B. PearsonT. Choi
  • Biology, Chemistry
    Proceedings of the National Academy of Sciences of the United States of America
  • 1993
RNase protection analysis of human APP mRNAs demonstrated appropriate splicing of the primary APP transcript in ES cells and in the brain of a transgenic animal, useful for elucidating the function of the various APP isoforms in vivo.

Introduction and expression of the 400 kilobase precursor amyloid protein gene in transgenic mice

A 650 kilobase yeast artificial chromosome that contains the entire, unrearranged 400 kb human APP gene into mouse embryonic stem (ES) cells by lipid–mediated transfection and this transgenic strategy may prove invaluable for the development of mouse models for AD and DS.