Focally Elevated Creatine Detected in Amyloid Precursor Protein (APP) Transgenic Mice and Alzheimer Disease Brain Tissue

Robert Julian,Kathleen M. Gough,Marc R. Del Bigio,David Westaway,Jin Yang,Adriana Szeghalmi,Margaret Rak,Meghan Gallant

doi:10.1074/jbc.c500244200

Robert Julian, Kathleen M. Gough

Open Access

https://doi.org/10.1074/jbc.c500244200

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Abstract

The creatine/phosphocreatine system, regulated by creatine kinase, plays an important role in maintaining energy balance in the brain. Energy metabolism and the function of creatine kinase are known to be affected in Alzheimer diseased brain and in cells exposed to the beta-amyloid peptide. We used infrared microspectroscopy to examine hippocampal, cortical, and caudal tissue from 21-89-week-old transgenic mice expressing doubly mutant (K670N/M671L and V717F) amyloid precursor protein and displaying robust pathology from an early age. Microcrystalline deposits of creatine, suggestive of perturbed energetic status, were detected by infrared microspectroscopy in all animals with advanced plaque pathology. Relatively large creatine deposits were also found in hippocampal sections from post-mortem Alzheimer diseased human brain, compared with hippocampus from non-demented brain. We therefore speculate that this molecule is a marker of the disease process.

Highlights

Alzheimer disease (AD)6 is a progressive neurodegenerative disorder characterized by memory loss and dementia
The Cr-PCr system plays a crucial role in energy metabolism, maintaining ATP homeostasis through the enzymatic additional or removal of phosphate [9]
While there is no obvious reason for Cr to be deposited in the AD brains, it is important to note that reduced brain metabolism is almost always associated with AD and other forms of dementia [3]

Summary

Introduction

Alzheimer disease (AD) is a progressive neurodegenerative disorder characterized by memory loss and dementia. We report here the novel and unexpected discovery of large creatine (Cr) deposits in the hippocampi and cortex of transgenic AD mice and in post-mortem sections of human AD hippocampus. Following our initial identification of Cr deposits in small IR maps of brain tissue from the four 47-week-old and one 21-week-old TgCRND8, we mapped the complete hippocampus in sections from sixteen animals (Tg and non-Tg littermates from two different mouse lines expressing the same double mutant form of APP695) and discovered extensive Cr load in all Tg mice. Large deposits of Cr were identified in hippocampal sections from post-mortem AD human brain These deposits are absent or significantly lower in age-matched control mice and in non-demented post-mortem human hippocampus; we speculate that their presence is an important and hitherto unsuspected marker of the disease process

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