Dataset Information

Misprocessing of APP and accumulation of β-Amyloid causes early alteration of pathways implicated in late-onset Alzheimer disease.

ABSTRACT: Genome-wide association studies (GWAS) have identified genes in lipid metabolism,inflammation and vesicular trafficking pathways as risk factors for late onset Alzheimer disease (LOAD). The mechanism by which they cause AD and their relationship to the amyloid cascade affected by genes causing early onset familial AD is unknown. Unproven hypotheses are that these LOAD genes modulate the amyloid cascade itself or downstream targets affected by this cascade.If so, it is likely that these genes and/or other genes in the same pathways may show alterations in their expression as an early consequence of misprocessing of amyloid precursor protein (APP) and accumulation of amyloid β-peptides (Aβ). We report that in three independent APP transgenic mouse models of AD, multiple genes in lipid and inflammation pathways show very early changes in mRNA and protein expression. Many of these changes are reversed by treatment with LXR agonists, which regulate transcription of genes in lipid/inflammation pathways, and which we have previously shown can reverse the cognitive deficits and neuropathology in Tg2756 mice. These results suggest that changes in lipid and inflammation pathways are likely to be very early consequences of APP misprocessing and Aβ accumulation in AD. Moreover, genetic variants within these pathways might affect risk for AD by modulating this early response. These pathways are likely to contain biomarkers of early disease and targets for therapies.

ORGANISM(S): Mus musculus

PROVIDER: GSE31372 | GEO | 2014/08/12

SECONDARY ACCESSION(S): PRJNA145899

REPOSITORIES: GEO

ACCESS DATA

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Project description:Alzheimer’s disease (AD) is a chronic ageing related neurodegenerative disease which is characterized by loss of synapses and neurons in the vulnerable brain regions. Expression perturbations of amyloid β (Aβ) and tau protein in the brain are two hallmarks of AD. Aβ is abnormally generated from amyloid precursor protein (APP) which is broadly distributed in different brain regions including the hippocampus and cortex. It is believed that increased Aβ expression plays a causative role in the early stage of AD pathology. Aβ protein interacts with the signaling pathways that control the phosphorylation of the microtubule-associated protein tau, which eventually disrupts the neuronal circuitry as well as network connectivity leading to neurodegenerative processes observed in AD. In addition, substantial molecular and neurodegenerative changes occur in the initial stage of AD even before the cognitive symptoms are evident, which makes the early diagnosis of AD vital to any timely disease stabilization and treatment. However, despite myriad efforts and substantial progress in the field to decipher the molecular mechanisms of disease onset and its progression, specific causes underlying AD pathology remain ill-defined. There is an urgent need to identify novel mechanism based interventional approaches that can stop, or slow down, the progression of AD. Therefore, it is important to improve the knowledge of the early AD and have a better understanding of the underlying molecular mechanisms induced by Aβ. In this study, we performed comparative quantitative proteomics on different brain regions of 2.5 months old APP/PS1 mice (hippocampus, frontal cortex, parietal cortex and cerebellum) in order to investigate the early stage impact of AD. Although over 5000 proteins were identified in all regions, the proteome response across regions was greatly varied. As expected, the greatest proteome perturbation was detected in the hippocampus and frontal cortex (AD-susceptible brain regions), compared to only 155 changed proteins in the cerebellum (less vulnerable region to AD). Increased expression of APP protein was identified in all brain regions. The expression of the majority of the other proteins between hippocampus and cortex areas was not similar, highlighting differential effects of the disease on different brain regions. A series of AD associated markers and pathways were identified as overexpressed in the hippocampus including glutamatergic synapse, GABAergic synapse, retrograde endocannabinoid signaling, long-term potentiation, and calcium signaling. In contrast, the expression of same proteins and pathways was negatively regulated in frontal and parietal cortex regions. Additionally, an increased expression of proteins associated with the oxidative phosphorylation pathway in hippocampus was not evident in the two cortices. Interestingly, an increased expression of proteins involved with myelination, neurofilament cytoskeleton organization, and glutathione metabolism was identified in cortex areas, while these were reduced in the hippocampus. The results obtained from this study highlight important information on brain region specific protein expression changes occurring in the early stages of AD.

Dataset Information

Misprocessing of APP and accumulation of β-Amyloid causes early alteration of pathways implicated in late-onset Alzheimer disease.

Dataset's files

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets