The Alzheimer's Aβ peptide induces neurodegeneration and apoptotic cell death in transgenic mice

  title={The Alzheimer's A$\beta$ peptide induces neurodegeneration and apoptotic cell death in transgenic mice},
  author={Frank M LaFerla and Brad T Tinkle and Charles J. Bieberich and Christian C. Haudenschild and Gilbert Jay},
  journal={Nature Genetics},
To test whether the hypothesis that the Alzheimer's Aβ peptide is neurotoxic, we introduced a transgene into mice to direct expression of this peptide to neurons. We show that the transgene is expressed in brain regions which are severely affected in Alzheimer's disease resulting in extensive neuronal degeneration. Morphological and biochemical evidence indicates that the eventual death of these cells occurs by apoptosis. Coincident with the cell degeneration and cell death is the presence of a… 
Markers of apoptosis and models of programmed cell death in Alzheimer's disease.
This work has analyzed tau gene expression in primary neuronal cultures submitted to an apoptotic stress produced by excitotoxicity or serum deprivation and found that neurons expressing phosphorylated tau are more resistant to experimental apoptosis than neurons positively labeled for dephosphorylation of tau protein.
The effects of soluble Aβ oligomers on neurodegeneration in Alzheimer's disease.
A novel framework, the aging factor cascade hypothesis, is proposed in an attempt to integrate the new data and concepts that emerged from recent research to develop disease modifying therapies, in light of the low efficiency of AD therapies based on the amyloid cascade hypothesis.
Age-Dependent Neuronal and Synaptic Degeneration in Mice Transgenic for the C Terminus of the Amyloid Precursor Protein
It is reported here that aging APP-C100 transgenic mice exhibit profound degeneration of neurons and synapses in Ammon’s horn and the dentate gyrus of the hippocampal formation, and these findings show that APP- C100 is capable of causing some of the neuropathological features of AD.
Extracellular deposition of beta-amyloid upon p53-dependent neuronal cell death in transgenic mice.
This transgenic mouse model suggests that intracellular generation of the Abeta protein not only leads to the death of the neuron but may also functionally impair neighboring neurons as well, and offers a mechanism whereby neuritic plaques may be derived.
Death and survival of neuronal cells exposed to Alzheimer's insults
Humanin, a newly identified 24‐residue peptide, suppresses neuronal cell death by various FAD mutants and Aβ, whereas this factor has no effect on cytotoxicity from AD‐irrelevant insults.


Apoptosis is induced by beta-amyloid in cultured central nervous system neurons.
It is reported that synthetic A beta Ps trigger the degeneration of cultured neurons through activation of an apoptotic pathway, suggesting that apoptosis may play a role in the neuronal loss associated with Alzheimer disease.
Degeneration in vitro of post-mitotic neurons overexpressing the Alzheimer amyloid protein precursor
The results suggest that post-mitotic neurons are vulnerable to overexpressed APP, which undergoes aberrant processing to generate potentially amyloidogenic fragments.
Deposition of beta/A4 immunoreactivity and neuronal pathology in transgenic mice expressing the carboxyl-terminal fragment of the Alzheimer amyloid precursor in the brain.
Observations suggest that expression of abnormal carboxyl-terminal subfragments of beta APP in vivo may cause amyloidogenesis and specific neuropathology.
Deposits of amyloid beta protein in the central nervous system of transgenic mice.
Aggregates of the amyloid beta protein formed amyloids-like fibrils that are similar in appearance to those in the brains of patients with Alzheimer's disease.
Transgenic mice for the amyloid precursor protein 695 isoform have impaired spatial memory
A gene dosage effect of APP695 may account for the memory impairment but not the plaque formation associated with AD, according to preliminary neuropathological investigations.
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.
Amyloid β-protein deposition in tissues other than brain in Alzheimer's disease
The detection of amyloid β-protein deposits in non-neural tissues and blood vessels of Alzheimer's disease patients, including skin, subcutaneous tissue and intestine is reported, indicating that a principal feature of the disease process is expressed subclinically in tissues other than brain.
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.
Formation of amyloid-like fibrils in COS cells overexpressing part of the Alzheimer amyloid protein precursor
Results suggest that the formation of amyloid fibrils is an inherent characteristic of the C-terminal peptide of APP, and the present system provides a suitable model for the molecular dissection of the process of brain amyloidsogenesis.
Amyloid β-peptide is produced by cultured cells during normal metabolism
The unexpected identification of the 4K (Mr 4,000) Aβ and a truncated form of Aβ in media from cultures of primary cells and untransfected and β-APP-transfected cell lines grown under normal conditions provide the basis for using simple cell culture systems to identify drugs that block the formation or release of A β, the primary protein constituent of the senile plaques of Alzheimer's disease.