Association among Amyloid Plaque, Lipid, and Creatine in Hippocampus of TgCRND8 Mouse Model for Alzheimer Disease

Abstract

Amyloid peptide (A␤) aggregation in the brain is a characteristic feature of Alzheimer disease (AD). Previously, we reported the discovery of focally elevated creatine deposits in brain tissue from TgCRND8 mice, which express double mutant (K670N/M671L and V717F) amyloid protein precursor. In this study, frozen hippocampal tissue sections from 5-, 8-, 11-, 14-, and 17-month old TgCRND8 and littermate control mice were examined with Fourier transform infrared microspectroscopy to explore the distribution of lipid, creatine, and dense core plaque deposits. Lipid distribution throughout the hippocampus was similar in transgenic (Tg) and non-Tg littermates at all ages. Dense core plaques were always found to lie within a thin (30 -50 m) lipid envelope, confirmed by imaging through serial sections. Creatine deposits were found in all TgCRND8 mice; the extent of deposition increased with age. Minor creatine deposits appeared in the oldest littermate controls. Distribution in the serial sections showed moderate correlation between layers, slightly disturbed by the freeze/thaw process. Creatine deposits in Tg mice were not specifically co-localized with plaques or lipid halos. The dimension of the lipid envelope is comparable with that of the diffuse halo of nonaggregated amyloid, implying a dynamic association in vivo, postulated to have a significant role in the evolving neurotoxicity. Alzheimer disease (AD)6 is a slowly progressing, heterogeneous neurodegenerative disorder characterized by memory impairment, emotional imbalances, and dementia (1). The pathological hallmarks include extracellular deposits of amyloid peptides (A␤) derived from the amyloid precursor protein (APP), and neurofibrillary tangles formed within the neurons due to hyperphosphorylated tau protein (2). Spatial, temporal, and biochemical connections between A␤ deposits and hyperphosphorylated tau tangles are still debated (3, 4). A dynamic equilibrium between the aggregated A␤ and the possibly more toxic protofibrils, mediated by neuronal membrane lipids, has been demonstrated in vitro (5).Several theories have been developed to explain AD pathogenesis, including amyloid cascade, neurofibrillary tangle formation, oxidative stress and inflammation, although the exact mechanism that causes neuronal dysfunction and death remains unclear (6 -9). Reactive oxygen species and lipid peroxidation lead to oxidation of protein, DNA, and RNA (10). Although oxidative damage is believed to contribute to disease progression, an antioxidant diet that reduced oxidized end products did not reduce plaque load or slow learning impairment in APP mice (11).We have reported Fourier transform infrared (FTIR) and Raman analyses (12, 13) of brain sections from the TgCRND8 mouse model (14, 15), which expresses a double mutant form of human APP695 (K670N/M671L and V717F), and nontransgenic littermate controls. The position and intensity of the bands in an infrared (IR) spectrum reflect the biomolecular composition of tissue (12, 13, 16 -18). Our IR and Raman spectra reveal ...

Formation of Dynamic Soluble Surfactant-induced Amyloid β Peptide Aggregation Intermediates

“…Surfactants may also be considered as a model system for natural lipids that were found to be located around and within in vivo amyloid plaques (13,14) and revert A␤(1-42) aggregates to neurotoxic protofibrils (15). This underlines the significant role of lipids in the aggregation process.…”

“…Lipids are known to be associated with in vivo amyloid plaques (13,14). Several studies have also been devoted to the effects of lipids on A␤ aggregation pathways (15,16).…”

FTIR Imaging of Tissues: Techniques and Methods of Analysis

“…this process is observed in the dementia-related disorders and may indicate a disturbed function of mitochondrial creatine kinase catalysing creatine phosphorylation [130]. A few creatine deposits can appear in normal ageing (in > 14-month mice), but more than 30 deposits randomly distributed in the hippocampus were already detected in the 5-month tgCRNd8 brain, and this number increased significantly with ageing of animals with Ad disease [131]. the comprehensive analysis of IR images recorded for the same animal model has given an insight into chemical composition of the two types of the Aβ deposit, namely dense-core and diffuse amyloid plaques [132].…”

Multivariate Analysis for Fourier Transform Infrared Spectra of Complex Biological Systems and Processes

“…Making it possible to obtain a sample biochemical fingerprint in a rapid and non destructive way, FTIR microspectroscopy is widely applied to the in situ characterization of cellular processes, such as cell maturation, differentiation, and reprogramming [3, 5-7, 25, 35], and to the detection of several diseases, as, for instance, cancer [13][14][15] and neurodegenerative disorders [10,11], whose onset is accompanied by changes in the composition and structure of several biomolecules.…”

“…In this way, FTIR microspectroscopy provides detailed information on several biological processes in situ, among which stem cell differentiation [1][2][3][4][5], somatic cell reprogramming [6], cell maturation [7,8], amyloid aggregation [9][10][11][12] and cancer onset and progression [13][14][15], making it possible to disclose the infrared response not only from single cells, but also from subcellular compartments [8,16,17].…”