Abstract:
BACKGROUND:The application of advanced sequencing technologies and improved mass-spectrometry platforms revealed significant changes in gene expression and lipids in Alzheimer's disease (AD) brain. The results so far have prompted further research using "multi-omics" approaches. These approaches become particularly relevant, considering the inheritance of APOEε4 allele as a major genetic risk factor of AD, disease protective effect of APOEε2 allele, and a major role of APOE in brain lipid metabolism. METHODS:Postmortem brain samples from inferior parietal lobule genotyped as APOEε2/c (APOEε2/carriers), APOEε3/3, and APOEε4/c (APOEε4/carriers), age- and gender-matched, were used to reveal APOE allele-associated changes in transcriptomes and lipidomes. Differential gene expression and co-expression network analyses were applied to identify up- and downregulated Gene Ontology (GO) terms and pathways for correlation to lipidomics data. RESULTS:Significantly affected GO terms and pathways were determined based on the comparisons of APOEε2/c datasets to those of APOEε3/3 and APOEε4/c brain samples. The analysis of lists of genes in highly correlated network modules and of those differentially expressed demonstrated significant enrichment in GO terms associated with genes involved in intracellular proteasomal and lysosomal degradation of proteins, protein aggregates and organelles, ER stress, and response to unfolded protein, as well as mitochondrial function, electron transport, and ATP synthesis. Small nucleolar RNA coding units important for posttranscriptional modification of mRNA and therefore translation and protein synthesis were upregulated in APOEε2/c brain samples compared to both APOEε3/3 and APOEε4/c. The analysis of lipidomics datasets revealed significant changes in ten major lipid classes (exclusively a decrease in APOEε4/c samples), most notably non-bilayer-forming phosphatidylethanolamine and phosphatidic acid, as well as mitochondrial membrane-forming lipids. CONCLUSIONS:The results of this study, despite the advanced stage of AD, point to the significant differences in postmortem brain transcriptomes and lipidomes, suggesting APOE allele associated differences in pathogenic mechanisms. Correlations within and between lipidomes and transcriptomes indicate coordinated effects of changes in the proteasomal system and autophagy-canonical and selective, facilitating intracellular degradation, protein entry into ER, response to ER stress, nucleolar modifications of mRNA, and likely myelination in APOEε2/c brains. Additional research and a better knowledge of the molecular mechanisms of proteostasis in the early stages of AD are required to develop more effective diagnostic approaches and eventually efficient therapeutic strategies.
journal_name
Alzheimers Res Therjournal_title
Alzheimer's research & therapyauthors
Lefterov I,Wolfe CM,Fitz NF,Nam KN,Letronne F,Biedrzycki RJ,Kofler J,Han X,Wang J,Schug J,Koldamova Rdoi
10.1186/s13195-019-0558-0subject
Has Abstractpub_date
2019-12-30 00:00:00pages
113issue
1issn
1758-9193pii
10.1186/s13195-019-0558-0journal_volume
11pub_type
杂志文章abstract:INTRODUCTION:Weight loss has been described in 20% to 45% of patients with Alzheimer's disease (AD) and has been associated with adverse outcomes. Various mechanisms for weight loss in AD patients have been proposed, though none has been proven. This study aimed to elucidate a mechanism of weight loss in AD patients by...
journal_title:Alzheimer's research & therapy
pub_type: 杂志文章
doi:10.1186/s13195-015-0098-1
更新日期:2015-04-06 00:00:00
abstract:BACKGROUND:Alzheimer's disease (AD) pathophysiology is mostly (>95%) not inherited in a Mendelian fashion. Such sporadic AD (sAD) forms do not exhibit familial aggregation and are characterized by complex genetic inheritance. Growing evidence indicates that multiple genes contribute to sAD-characteristic endophenotypes...
journal_title:Alzheimer's research & therapy
pub_type: 杂志文章
doi:10.1186/alzrt165
更新日期:2013-03-18 00:00:00
abstract:BACKGROUND:Disclosure of amyloid positron emission tomography (PET) results to individuals without dementia has become standard practice in secondary prevention trials and also increasingly occurs in clinical practice. However, this is controversial given the current lack of understanding of the predictive value of a P...
journal_title:Alzheimer's research & therapy
pub_type: 杂志文章
doi:10.1186/s13195-018-0398-3
更新日期:2018-07-28 00:00:00
abstract:BACKGROUND:[18F]FDG-PET hypometabolism patterns are indicative of different neurodegenerative conditions, even from the earliest disease phase. This makes [18F]FDG-PET a valuable tool in the diagnostic workup of neurodegenerative diseases. The utility of [18F]FDG-PET in dementia with Lewy bodies (DLB) needs further val...
journal_title:Alzheimer's research & therapy
pub_type: 杂志文章
doi:10.1186/s13195-019-0473-4
更新日期:2019-02-23 00:00:00
abstract:BACKGROUND:Cerebrovascular pathology, quantified by white matter lesions (WML), is known to affect cognition in aging, and is associated with an increased risk of dementia. The present study aimed to investigate whether higher functional connectivity in cognitive control networks mitigates the detrimental effect of WML...
journal_title:Alzheimer's research & therapy
pub_type: 杂志文章
doi:10.1186/s13195-018-0434-3
更新日期:2018-10-27 00:00:00
abstract:BACKGROUND:Alzheimer's disease (AD) is a progressive neurodegenerative disorder and the most common cause of dementia in the elderly population. In this study, we used the APP/PS1 transgenic mouse model to explore the feasibility of using diffusion kurtosis imaging (DKI) as a tool for the early detection of microstruct...
journal_title:Alzheimer's research & therapy
pub_type: 杂志文章
doi:10.1186/s13195-017-0329-8
更新日期:2018-01-09 00:00:00
abstract:INTRODUCTION:Alzheimer's disease (AD) is increasing in frequency as the global population ages. Five drugs are approved for treatment of AD, including four cholinesterase inhibitors and an N-methyl-D-aspartate (NMDA)-receptor antagonist. We have an urgent need to find new therapies for AD. METHODS:We examined Clinical...
journal_title:Alzheimer's research & therapy
pub_type: 杂志文章
doi:10.1186/alzrt269
更新日期:2014-07-03 00:00:00
abstract:BACKGROUND:Given the growing older population worldwide, and the associated increase in age-related diseases, such as Alzheimer's disease (AD), investigating non-invasive methods to ameliorate or even prevent cognitive decline in prodromal AD is highly relevant. Previous studies suggest transcranial direct current stim...
journal_title:Alzheimer's research & therapy
pub_type: 杂志文章
doi:10.1186/s13195-020-00692-5
更新日期:2020-11-07 00:00:00
abstract:INTRODUCTION:There have been recent reports about a decline in dementia incidence, but only little is known about trends in the mortality of patients with dementia. Only the simultaneous analysis of both trends can inform whether the reported decline in dementia has led to a compression of dementia into higher ages. M...
journal_title:Alzheimer's research & therapy
pub_type: 杂志文章
doi:10.1186/s13195-015-0146-x
更新日期:2015-11-05 00:00:00
abstract:INTRODUCTION:The long-term efficacy and safety of donepezil 10 mg in patients with dementia with Lewy bodies (DLB) were investigated in a 52-week Phase 3 trial. METHODS:This 52-week study consisted of 16-week randomized placebo-controlled (RCT) and 36-week open-label extension phases. Of 142 DLB patients enrolled in t...
journal_title:Alzheimer's research & therapy
pub_type: 杂志文章
doi:10.1186/s13195-014-0081-2
更新日期:2015-02-03 00:00:00
abstract:BACKGROUND:Targeting the expression of genes has emerged as a potentially viable therapeutic approach to human disease. In Alzheimer's disease, therapies that silence the expression of tau could be a viable strategy to slow disease progression. METHODS:We produced a novel strain of transgenic mice that could be used t...
journal_title:Alzheimer's research & therapy
pub_type: 杂志文章
doi:10.1186/s13195-016-0202-1
更新日期:2016-09-05 00:00:00
abstract:BACKGROUND:Optical coherence tomography (OCT) of the retina is a fast and easily accessible tool for the quantification of retinal structural measurements. Multiple studies show that patients with Alzheimer's disease (AD) exhibit thinning in several retinal layers compared to age-matched controls. Subjective cognitive ...
journal_title:Alzheimer's research & therapy
pub_type: 杂志文章
doi:10.1186/s13195-020-00602-9
更新日期:2020-03-31 00:00:00
abstract::Therapeutic products that depend on the use of an in vitro diagnostic biomarker test to confirm their effectiveness are increasingly being developed. Use of biomarkers is particularly meaningful in the context of selecting the patient population where the therapeutic treatment is believed to be efficacious (patient en...
journal_title:Alzheimer's research & therapy
pub_type: 杂志文章,评审
doi:10.1186/alzrt142
更新日期:2012-10-17 00:00:00
abstract:BACKGROUND:Synaptic dysfunction contributes to cognitive impairment in Alzheimer's disease and may be countered by increased intake of nutrients that target brain phospholipid metabolism. In this study, we explored whether the medical food Souvenaid affects brain phospholipid metabolism in patients with Alzheimer's dis...
journal_title:Alzheimer's research & therapy
pub_type: 杂志文章,随机对照试验
doi:10.1186/s13195-017-0286-2
更新日期:2017-07-26 00:00:00
abstract:BACKGROUND:Intracerebral inoculation of extracts from post-mortem human Alzheimer's disease brains into mice produces a prion-like spreading effect of amyloid-β. The differences observed between these extracts and the synthetic peptide, in terms of amyloid-β internalization and seed and cell-to-cell transmission of cyt...
journal_title:Alzheimer's research & therapy
pub_type: 杂志文章
doi:10.1186/s13195-019-0513-0
更新日期:2019-06-29 00:00:00
abstract::Recent trials of statins produced no benefit for subjects with Alzheimer's disease. These negative studies add to a growing list of negative clinical trials. These data point to a need for reevaluating the pathophysiology of late-onset Alzheimer's disease. Late-onset Alzheimer's disease might result from the cumulativ...
journal_title:Alzheimer's research & therapy
pub_type: 社论
doi:10.1186/alzrt101
更新日期:2012-01-16 00:00:00
abstract::Lewy body dementia (LBD), including dementia with Lewy bodies and Parkinson's disease dementia, affects over a million people in the USA and has a substantial impact on patients, caregivers, and society. Symptomatic treatments for LBD, which can include cognitive, neuropsychiatric, autonomic, sleep, and motor features...
journal_title:Alzheimer's research & therapy
pub_type: 杂志文章,评审
doi:10.1186/s13195-020-00703-5
更新日期:2020-10-29 00:00:00
abstract:BACKGROUND:The Centiloid scale has been developed to standardize measurements of amyloid PET imaging. Reference cut-off values of this continuous measurement enable the consistent operationalization of decision-making for multicentre research studies and clinical trials. In this study, we aimed at deriving reference Ce...
journal_title:Alzheimer's research & therapy
pub_type: 杂志文章
doi:10.1186/s13195-019-0478-z
更新日期:2019-03-21 00:00:00
abstract:BACKGROUND:Disturbed amyloid precursor protein (APP) processing is considered to be central to the pathogenesis of Alzheimer's disease (AD). The autosomal dominant form of the disease, familial AD (FAD), may serve as a model for the sporadic form of AD. In FAD the diagnosis of AD is reliable and presymptomatic individu...
journal_title:Alzheimer's research & therapy
pub_type: 杂志文章
doi:10.1186/s13195-017-0234-1
更新日期:2017-02-16 00:00:00
abstract::The Alzheimer's Drug Discovery Foundation's 13th International Conference on Alzheimer's Drug Discovery was held on 10-11 September 2012 in Jersey City, NJ, USA. This meeting report provides an overview of Alzheimer's Drug Discovery Foundation-funded programs, ranging from novel biomarkers to accelerate clinical devel...
journal_title:Alzheimer's research & therapy
pub_type: 杂志文章
doi:10.1186/alzrt159
更新日期:2013-02-04 00:00:00
abstract:BACKGROUND:The retina and brain share many neuronal and vasculature characteristics. We investigated the retinal microvasculature in Alzheimer's disease (AD) and mild cognitive impairment (MCI) using optical coherence tomography angiography (OCTA). METHODS:In this cross-sectional study, 24 AD participants, 37 MCI part...
journal_title:Alzheimer's research & therapy
pub_type: 杂志文章
doi:10.1186/s13195-020-00724-0
更新日期:2020-12-04 00:00:00
abstract:BACKGROUND:In patients with amyloid-positive mild cognitive impairment (MCI), neurodegenerative biomarkers such as medial temporal lobe atrophy (MTA) are useful to predict disease progression to dementia. Although posterior atrophy (PA) is a well-known neurodegenerative biomarker of Alzheimer's disease, little is known...
journal_title:Alzheimer's research & therapy
pub_type: 杂志文章
doi:10.1186/s13195-017-0326-y
更新日期:2017-12-16 00:00:00
abstract:BACKGROUND:Amyloid pathology, which is one of the characteristics of Alzheimer's disease (AD), results from altered metabolism of the beta-amyloid (Aβ) peptide in terms of synthesis, clearance, or aggregation. A decrease in cerebrospinal fluid (CSF) level Aβ1-42 is evident in AD, and the CSF ratio Aβ42/Aβ40 has recentl...
journal_title:Alzheimer's research & therapy
pub_type: 杂志文章
doi:10.1186/s13195-020-00696-1
更新日期:2020-10-02 00:00:00
abstract:BACKGROUND:Dementia has been presenting an imminent public health challenge worldwide. Studies have shown a combination of cognitive and physical trainings may have synergistic value for improving cognitive functions. Daily functional tasks are innately cognitive demanding and involve components found in common exercis...
journal_title:Alzheimer's research & therapy
pub_type: 杂志文章,随机对照试验
doi:10.1186/s13195-019-0548-2
更新日期:2019-12-04 00:00:00
abstract::Identification of therapeutic targets based on novel mechanistic studies is urgently needed for neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, and prion disease. Multiple lines of evidence have emerged to suggest that inhibition of the stress-induced endoplasmic reticulum kinase PERK (pro...
journal_title:Alzheimer's research & therapy
pub_type: 杂志文章
doi:10.1186/alzrt260
更新日期:2014-05-29 00:00:00
abstract:BACKGROUND:Metabolic alterations, related to cerebral glucose metabolism, brain insulin resistance, and age-induced mitochondrial dysfunction, play an important role in Alzheimer's disease (AD) on both the systemic and central nervous system level. To study the extent and significance of these alterations in AD, quanti...
journal_title:Alzheimer's research & therapy
pub_type: 杂志文章
doi:10.1186/s13195-019-0551-7
更新日期:2019-11-28 00:00:00
abstract:INTRODUCTION:There is a great need for quick tests that identify treatment response in Alzheimer's disease (AD) to determine who benefits from the treatment. In this study, A Quick Test of cognitive speed (AQT) was compared with the mini-mental state examination (MMSE) in the evaluation of treatment outcome in AD. MET...
journal_title:Alzheimer's research & therapy
pub_type: 杂志文章
doi:10.1186/alzrt53
更新日期:2010-10-15 00:00:00
abstract:BACKGROUND:Synapse damage and loss are fundamental to the pathophysiology of Alzheimer's disease (AD) and lead to reduced cognitive function. The goal of this review is to address the challenges of forging new clinical development approaches for AD therapeutics that can demonstrate reduction of synapse damage or loss. ...
journal_title:Alzheimer's research & therapy
pub_type: 杂志文章,评审
doi:10.1186/s13195-020-00588-4
更新日期:2020-03-02 00:00:00
abstract:BACKGROUND:Imaging agents capable of quantifying the brain's tau aggregates will allow a more precise staging of Alzheimer's disease (AD). The aim of the present study was to examine the in vitro properties as well as the in vivo kinetics, using gold standard methods, of the novel positron emission tomography (PET) tau...
journal_title:Alzheimer's research & therapy
pub_type: 杂志文章
doi:10.1186/s13195-018-0402-y
更新日期:2018-07-31 00:00:00
abstract:BACKGROUND:Neuroinflammation has gained increasing attention as a potential contributing factor in Alzheimer's disease (AD) pathology. A clinical cerebrospinal fluid biomarker capable of monitoring this process during the course of the disease has yet to emerge, chiefly owing to contradictory research findings. In this...
journal_title:Alzheimer's research & therapy
pub_type: 杂志文章
doi:10.1186/s13195-018-0353-3
更新日期:2018-02-26 00:00:00