iTRAQ Analysis of Complex Proteome Alterations in 3xTgAD Alzheimer's Mice: Understanding the Interface between Physiology and Disease

Abstract

Alzheimer's disease (AD) is characterized by progressive cognitive impairment associated with accumulation of amyloid β-peptide, synaptic degeneration and the death of neurons in the hippocampus, and temporal, parietal and frontal lobes of the cerebral cortex. Analysis of postmortem brain tissue from AD patients can provide information on molecular alterations present at the end of the disease process, but cannot discriminate between changes that are specifically involved in AD versus those that are simply a consequence of neuronal degeneration. Animal models of AD provide the opportunity to elucidate the molecular changes that occur in brain cells as the disease process is initiated and progresses. To this end, we used the 3xTgAD mouse model of AD to gain insight into the complex alterations in proteins that occur in the hippocampus and cortex in AD. The 3xTgAD mice express mutant presenilin-1, amyloid precursor protein and tau, and exhibit AD-like amyloid and tau pathology in the hippocampus and cortex, and associated cognitive impairment. Using the iTRAQ stable-isotope-based quantitative proteomic technique, we performed an in-depth proteomic analysis of hippocampal and cortical tissue from 16 month old 3xTgAD and non-transgenic control mice. We found that the most important groups of significantly altered proteins included those involved in synaptic plasticity, neurite outgrowth and microtubule dynamics. Our findings have elucidated some of the complex proteome changes that occur in a mouse model of AD, which could potentially illuminate novel therapeutic avenues for the treatment of AD and other neurodegenerative disorders.

Rare autosomal copy number variations in early-onset familial Alzheimer’s disease

“…Gap junction proteins are specialized in intercellular connection between various cell types, notably at the synapses and is associated with both neuroprotective 38 and neurodestructive 39 functions. ERMP1 has not been characterized in great detail, but encodes a zinc-dependent endoplasmic reticulum metallopeptidase, with decreased expression in a transgenic AD mouse model; 40 higher ERMP1 expression has been reported in epilepsy mouse models. 41 Two affected siblings from family ND2 (onset ages: 52 and 56, APOE-e4 negative) with no unaffected siblings, carry FAD-CNV2 (240-kb gain), which overlaps EVC, EVC2 and CRMP1.…”

Proteomic analysis of cells exposed to prefibrillar aggregates of HypF-N

“…In Table 3 a comparison between the protein identified in our study and the proteins identified in other studies is shown, indicating that there is a general response of cells to toxic aggregates that is not sequence specific [12,13,30,31,32]. Actually, changes in the expression levels of Gapdh, actin, tubulin and heat shock proteins have frequently been reported in amyloid-linked proteomic studies possibly because they are related to a generic response to stress conditions [33] such as that associated with the growth of amyloid aggregates.…”

“…Such a complex pattern of cell impairment makes proteomics one of the most useful tools to integrate these modifications into a whole systematic picture. The reports that recently appeared on the proteomic analysis of amyloid diseases such as Alzheimer's disease, Parkinson's disease and others have provided valuable data on some cell modifications allowing to explain, at least in part, cell impairment in these diseases [12][13][14][15][16]. Proteomic studies provided useful information on the changes in pattern of protein expression in cells exposed to toxic aggregates of specific peptides/proteins found aggregated in the corresponding diseases.…”

Physico-chemical characterization of beta-amyloid oligomers and study of their function in biological processes at molecular level

“…The binding affinities of other interacting partners to the APP or A␤ peptide, characterized with K d values also in the nanomolar range, suggest the pathological relevance of these interactions (52)(53)(54). Recently, proteomic analysis of hippocampal and cortical tissue from an animal model of AD has been performed where the most important groups of significantly altered proteins included those involved in synaptic plasticity, neurite outgrowth, and microtubule dynamics (55). Moreover, the levels of both tubulin and TPPP/p25 were found to increase both in the cortex and the hippocampus as compared with that of control samples (55), and the increase of TPPP/p25 level was similar to the increase of the ␣-synuclein level as well as that of the Tau level (55).…”

“…Recently, proteomic analysis of hippocampal and cortical tissue from an animal model of AD has been performed where the most important groups of significantly altered proteins included those involved in synaptic plasticity, neurite outgrowth, and microtubule dynamics (55). Moreover, the levels of both tubulin and TPPP/p25 were found to increase both in the cortex and the hippocampus as compared with that of control samples (55), and the increase of TPPP/p25 level was similar to the increase of the ␣-synuclein level as well as that of the Tau level (55). However, our data offer the first evidence to the direct binding of TPPP/p25 to A␤ 42 oligomer, which is stronger than that of the A␤ 42 to ␣-synuclein.…”