Distinctive RNA Expression Profiles in Blood Associated With Alzheimer Disease After Accounting for White Matter Hyperintensities

Bai, Zhouxian; Stamova, Boryana; Xu, Huichun; Ander, Bradley P.; Wang, Jiajia; Jickling, Glen C.; Zhan, Xinhua; Liu, Dazhi; Han, Guangchun; Jin, Lee Way; Lei, Hongxing; Sharp, Frank R.

doi:10.1097/wad.0000000000000022

Cited by 48 publications

(30 citation statements)

References 43 publications

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“…CTSD level was decreased in bone marrow-derived monocytes isolated from AD patients ( Tian et al, 2014 ). CTSD mRNA expression was upregulated in whole blood of AD patients ( Bai et al, 2014 ). On the other hand, CTSD is downregulated on both mRNA and protein levels in skin fibroblasts from AD patients ( Urbanelli et al, 2008 ).…”

Section: Biological Mechanisms Linking Autophagy and Admentioning

confidence: 99%

Autophagy and Alzheimer’s Disease: From Molecular Mechanisms to Therapeutic Implications

Uddin

Stachowiak

Mamun

et al. 2018

Front. Aging Neurosci.

319

247

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Alzheimer’s disease (AD) is the most common cause of progressive dementia in the elderly. It is characterized by a progressive and irreversible loss of cognitive abilities and formation of senile plaques, composed mainly of amyloid β (Aβ), and neurofibrillary tangles (NFTs), composed of tau protein, in the hippocampus and cortex of afflicted humans. In brains of AD patients the metabolism of Aβ is dysregulated, which leads to the accumulation and aggregation of Aβ. Metabolism of Aβ and tau proteins is crucially influenced by autophagy. Autophagy is a lysosome-dependent, homeostatic process, in which organelles and proteins are degraded and recycled into energy. Thus, dysfunction of autophagy is suggested to lead to the accretion of noxious proteins in the AD brain. In the present review, we describe the process of autophagy and its importance in AD. Additionally, we discuss mechanisms and genes linking autophagy and AD, i.e., the mTOR pathway, neuroinflammation, endocannabinoid system, ATG7, BCL2, BECN1, CDK5, CLU, CTSD, FOXO1, GFAP, ITPR1, MAPT, PSEN1, SNCA, UBQLN1, and UCHL1. We also present pharmacological agents acting via modulation of autophagy that may show promise in AD therapy. This review updates our knowledge on autophagy mechanisms proposing novel therapeutic targets for the treatment of AD.

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Section: Biological Mechanisms Linking Autophagy and Admentioning

confidence: 99%

Autophagy and Alzheimer’s Disease: From Molecular Mechanisms to Therapeutic Implications

Uddin

Stachowiak

Mamun

et al. 2018

Front. Aging Neurosci.

319

247

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“…Based upon the above considerations, and based upon genomic studies of blood of AD patients showing evidence of inflammation, oxidative stress and hypoxia (Bai et al, 2014 ), the hypothesis was developed that several systemic factors act together to produce AD (Zhan et al, 2015a ). There must be some cause of inflammation, it was reasoned that either an infectious agent or molecules from infectious agents might be important in causing AD, in particular lipopolysaccharide (LPS) which is found in the outer wall of all Gram-negative bacteria.…”

Section: Lps In Human Ad Brainmentioning

confidence: 99%

Lipopolysaccharide Associates with Amyloid Plaques, Neurons and Oligodendrocytes in Alzheimer’s Disease Brain: A Review

Zhan

Stamova

Sharp

2018

Front. Aging Neurosci.

Self Cite

255

229

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This review proposes that lipopolysaccharide (LPS, found in the wall of all Gram-negative bacteria) could play a role in causing sporadic Alzheimer’s disease (AD). This is based in part upon recent studies showing that: Gram-negative E. coli bacteria can form extracellular amyloid; bacterial-encoded 16S rRNA is present in all human brains with over 70% being Gram-negative bacteria; ultrastructural analyses have shown microbes in erythrocytes of AD patients; blood LPS levels in AD patients are 3-fold the levels in control; LPS combined with focal cerebral ischemia and hypoxia produced amyloid-like plaques and myelin injury in adult rat cortex. Moreover, Gram-negative bacterial LPS was found in aging control and AD brains, though LPS levels were much higher in AD brains. In addition, LPS co-localized with amyloid plaques, peri-vascular amyloid, neurons, and oligodendrocytes in AD brains. Based upon the postulate LPS caused oligodendrocyte injury, degraded Myelin Basic Protein (dMBP) levels were found to be much higher in AD compared to control brains. Immunofluorescence showed that the dMBP co-localized with β amyloid (Aβ) and LPS in amyloid plaques in AD brain, and dMBP and other myelin molecules were found in the walls of vesicles in periventricular White Matter (WM). These data led to the hypothesis that LPS acts on leukocyte and microglial TLR4-CD14/TLR2 receptors to produce NFkB mediated increases of cytokines which increase Aβ levels, damage oligodendrocytes and produce myelin injury found in AD brain. Since Aβ1–42 is also an agonist for TLR4 receptors, this could produce a vicious cycle that accounts for the relentless progression of AD. Thus, LPS, the TLR4 receptor complex, and Gram-negative bacteria might be treatment or prevention targets for sporadic AD.

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“…It has been suggested to be a toxicity modulator in Alzheimer's disease (Ghosh and Giese 2015). RNA expression of CAMK2G is altered in AD blood versus control (Bai et al 2014). Noteworthy, CAMK2G expression is also altered in brain tissue of TREM2 KO mice, linking it to the most prominent immune gene risk factor for AD (Carbajosa et al 2018).…”

Section: Controlmentioning

confidence: 99%

Quantitative proteomics of synaptosome S‐nitrosylation in Alzheimer’s disease

Wijasa

Sylvester

Brocke‐Ahmadinejad

et al. 2019

Journal of Neurochemistry

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Increasing evidence suggests that both synaptic loss and neuroinflammation constitute early pathologic hallmarks of Alzheimer’s disease. A downstream event during inflammatory activation of microglia and astrocytes is the induction of nitric oxide synthase type 2, resulting in an increased release of nitric oxide and the post‐translational S‐nitrosylation of protein cysteine residues. Both early events, inflammation and synaptic dysfunction, could be connected if this excess nitrosylation occurs on synaptic proteins. In the long term, such changes could provide new insight into patho‐mechanisms as well as biomarker candidates from the early stages of disease progression. This study investigated S‐nitrosylation in synaptosomal proteins isolated from APP/PS1 model mice in comparison to wild type and NOS2−/− mice, as well as human control, mild cognitive impairment and Alzheimer’s disease brain tissues. Proteomics data were obtained using an established protocol utilizing an isobaric mass tag method, followed by nanocapillary high performance liquid chromatography tandem mass spectrometry. Statistical analysis identified the S‐nitrosylation sites most likely derived from an increase in nitric oxide (NO) in dependence of presence of AD pathology, age and the key enzyme NOS2. The resulting list of candidate proteins is discussed considering function, previous findings in the context of neurodegeneration, and the potential for further validation studies.

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Distinctive RNA Expression Profiles in Blood Associated With Alzheimer Disease After Accounting for White Matter Hyperintensities

Cited by 48 publications

References 43 publications

Autophagy and Alzheimer’s Disease: From Molecular Mechanisms to Therapeutic Implications

Autophagy and Alzheimer’s Disease: From Molecular Mechanisms to Therapeutic Implications

Lipopolysaccharide Associates with Amyloid Plaques, Neurons and Oligodendrocytes in Alzheimer’s Disease Brain: A Review

Quantitative proteomics of synaptosome S‐nitrosylation in Alzheimer’s disease

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