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S3‐03‐03: Functional correlations of intracellular Aβ peptide in transgenic mouse models
Author(s) -
Delatour Benoît,
Myriam L.Y.,
Duyckaerts Charles
Publication year - 2011
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2011.05.2371
Subject(s) - intracellular , genetically modified mouse , transgene , amyloid (mycology) , amyloid beta , beta (programming language) , biology , amyloidosis , neuroscience , disease , pathology , medicine , psychology , endocrinology , microbiology and biotechnology , biochemistry , gene , computer science , programming language
Background: Alzheimer’s disease (AD) is characterized by accumulation of extracellular amyloid plaques and the presence of intracellular neurofibrillary tangles. There is increasing evidence that Aß peptidesaccumulate also inside neurons, in addition to thewell-known parenchymal extracellular amyloid deposition and it has been hypothesized that this represents one of the earliest events triggering the neurodegenerative cascade. Transgenic mice have been proven to be valuable systems to model early intraneuronal Aß accumulation and the resulting pathological consequences. Methods: Transgenic AD mouse models (APP/PS1KI, 5XFAD, TBA2) were used to investigate if significant increases in the amount of diverse Aß species within neurons coincided with neuron loss in the respective brain regions. The presence of extracellular amyloid plaques and intraneuronal Aß accumulations was assessed by immunohistochemical stainings using antibodies against a variety of Aß peptides. Design-based stereology was used to quantify neuron numbers in transgenic mouse brains harbouring either only extracellular, or extraand intracellular Aß pathology.Results:No significant neuron loss was detected in brain regions where only extracellular plaque deposition has been detected. The presence of intracellular Aß, however, coincided with significantly reduced neuron numbers in diverse brain regions like frontal cortex, CA1 or cholinergic brain stem nuclei in APP/ PS1KI mice or cortical layer 5 in 5XFADmice. In addition, the intracellular expression of truncated Aß3-42 resulted in massive neurological impairments and abundant neuronal loss in TBA2 mice. These results lead to the assumption that extracellular Aß pathology does not significantly contribute to neuron death. Conclusions: In summary, these observations support a pivotal role of intraneuronal Aß as a major trigger in ADtypicalneurodegeneration and neuron loss, whereas plaques might represent ‘wastebins’ for toxic peptides. The link to Tau is presently not fully understood.