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Updated: Apr 28, 2026

A Phenotyping Regimen for Genetically Modified Mice Used to Study Genes Implicated in Human Diseases of Aging

A Phenotyping Regimen for Genetically Modified Mice Used to Study Genes Implicated in Human Diseases of Aging

Published on: July 14, 2016

Humanized Klotho haplotypes cause widespread transcriptomic changes in mouse brain.

Anna L Tyler¹, Dylan Garceau¹, Kevin P Kotredes¹

¹The Jackson Laboratory for Mammalian Genetics, Bar Harbor, ME, USA.

Biorxiv : the Preprint Server for Biology

|April 27, 2026

Summary

This summary is machine-generated.

The human KLotho (KL) FC and VS alleles show widespread differences in brain gene expression by 12 months, impacting mitochondrial, ribosomal, and synaptic functions, potentially influencing Alzheimer's Disease risk.

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Area of Science:

Genetics and Aging Research
Neuroscience
Molecular Biology

Background:

The Klotho (KL) gene is implicated in aging and Alzheimer's Disease (AD) risk.
Two common human KL alleles, FC (major) and VS (minor), differ by two amino acid substitutions.
The functional impact of these human KL variants on brain aging and AD pathogenesis is not well understood.

Purpose of the Study:

To investigate the influence of human KL FC and VS alleles on brain aging and cognition.
To establish a mouse model expressing humanized KL alleles for functional studies.
To explore the molecular mechanisms by which KL variants may affect AD risk.

Main Methods:

Development of a novel mouse model with humanized KL FC or VS alleles.
RNA-sequencing (RNA-Seq) to analyze whole-brain transcriptomes in mice at 4 and 12 months of age.
Differential gene expression and exon usage analysis to identify molecular changes.

Main Results:

Widespread differences in brain gene expression were observed between FC and VS KL allele carriers at 12 months, but not at 4 months.
Key affected pathways included mitochondrial, ribosomal, and synaptic functions.
Differential splicing of synaptic genes and variations in glutamate receptors and amyloid precursor (APP) processing were identified.

Conclusions:

Human KL FC and VS haplotypes exert widespread effects on brain gene expression.
These KL variants impact biological processes relevant to AD pathogenesis, including synaptic function and APP processing.
The study provides evidence supporting the hypothesis that human KL haplotypes influence AD risk and pathogenesis.