Differential gene expression in human brain pericytes induced by amyloid‐β protein (original) (raw)
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Differential gene expression in human brain pericytes induced by amyloid-beta protein
Neuropathology and Applied Neurobiology, 2004
Cerebral amyloid angiopathy is one of the characteristics of Alzheimer's disease (AD) and this accumulation of fibrillar amyloid-b (Ab) in the vascular wall is accompanied by marked vascular damage. In vitro, Ab 1-40 carrying the 'Dutch' mutation (DAb 1-40 ) induces degeneration of cultured human brain pericytes (HBP). To identify possible intracellular mediators of Abinduced cell death, a comparative cDNA expression array was performed to detect differential gene expression of Ab-treated vs. untreated HBP. Messenger RNA expression of cyclin D1, integrin b4, defender against cell death-1, neuroleukin, thymosin b10, and integrin a5 were increased in DAb 1-40 -treated HBP, whereas insu-lin-like growth factor binding protein-2 mRNA expression was decreased. Corresponding protein expression was investigated in AD and control brains to explore a potential role for these proteins in pathological lesions of the AD brain. Cyclin D1 expression was increased in cerebral amyloid angiopathy and cells in a perivascular position, suggesting that the cell cycle may be disturbed during Ab-mediated degeneration of cerebrovascular cells. Moreover, cyclin D1 expression, but also that of integrin b4, defender against cell death-1, neuroleukin and thymosin b10 was found in a subset of senile plaques, suggesting a role for these proteins in the pathogenesis of senile plaques.
Background Alzheimer's disease (AD) is an age-related neurodegenerative disorder that is characterized by a progressive loss of higher cognitive functions. The brain of an individual with AD exhibits extracellular senile plaques (SPs) of aggregated amyloid-beta peptide (Aβ) and intracellular neurofibrillary tangles (NFTs). Given the critical role of neuronal transport of both proteins and organelles, it is not surprising that perturbation of microtubule-based transport may play a major role in the pathogenesis of AD.Materials and methods We used the cDNA subtraction methodology and in vitro neural cell culture analyses to study the meaning of the brain site-specific gene expression pattern in cerebral tissue obtained from AD patients and also from control subjects at autopsy.Results We observed that cytoskeleton-associated proteins were down-regulated in AD subjects. We also noted an altered expression of the microtubule-associated protein 1B (MAP1B), the heat-shock protein (HSP)-90 (a key chaperone molecule), the tripartite motif-containing proteins (TRIM)-32/37 (an anti apoptotic enzyme with ubiquitin-protein ligase activity) and the Reticulon-3 (a modulator of the amyloid-precursor-protein (APP) cleavage) in AD brains. Additional molecular- and cell-biological studies revealed that small interfering RNA (siRNA)-mediated down-regulation of MAP1B expression leads to neuronal cell death in vitro.Conclusion Altered expression of MAP1B, HSP90, TRIM32/37 and Reticulon-3 provides new clues by which the ubiquitin-proteasome-, the protein-chaperon- and the APP-processing systems are disturbed in AD, thus, leading to neuritic amyloid plaques and neurofibrillary tangles.
Experimental Neurology, 2012
a b s t r a c t Insulin-degrading enzyme MMP-9 SCARB1 MARCO Megalin LRP2 Astrocytes appear to be important mediators in the clearance of amyloid beta1-42 (Aβ), the key component of senile plaques characteristic of Alzheimer's disease (AD). Recently, we found the amyloid associated proteins (AAPs) α1-antichymotrypsin (ACT), apolipoprotein J and E (ApoJ and ApoE) and a mixture of serum amyloid P (SAP) and C1q (SAP-C1q) to modify Aβ-uptake by human astrocytes. Here we investigated the effect of oligomeric (Aβoligo) and fibrillar Aβ (Aβfib), alone and in combination with a panel of AAPs on the astrocytic expression of genes proposed to be involved in Aβ-uptake and degradation. Primary human astrocytes (isolated from non-demented control (n = 4) and AD patient (n = 4) brain specimens) were exposed to either Aβoligo or Aβfib preparations with or without the above mentioned AAPs. Quantitative gene expression analysis of Aβ-receptors Scavenger receptor B1 (SCARB1), macrophage receptor with collagenous structure (MARCO) and low density lipoprotein receptor related protein-2 (LRP2 or megalin) as well as of Aβdegrading enzymes neprilysin (NEP), insulin-degrading enzyme (IDE) and metalloproteinase-9 (MMP-9) was performed by real-time PCR. Basal expression of NEP, IDE and SCARB1 was easily detected whereas expression of MARCO, LRP2 and MMP-9 could only be detected upon pre-amplification. Basal expression of NEP, IDE and SCARB1 did not change upon exposure to Aβoligo or Aβfib alone in any of the investigated astrocyte cultures. Interestingly NEP expression was increased upon exposure to ApoE in combination with both Aβpreparations, and also SCARB1 expression was induced upon treatment with ApoE in combination with Aβfib in astrocytes from non-demented controls. Further, SAP-C1q increased SCARB1 expression in control astrocytes when combined with Aβoligo. These alterations were not found in astrocytes from AD patients. Thus, we conclude that Aβ alone apparently does not affect the astrocytic expression of IDE, NEP or SCARB1. However, NEP and SCARB1 expression is increased in astrocytes from non-demented subjects when exposed to Aβ combined with AAPs like ApoE. These astrocytic gene expression-regulatory mechanisms appear to be defective in AD and thus might contribute to the development and progression of AD pathology.
Scientific reports, 2017
Alzheimer's disease (AD) is the most common form of dementia, characterized by accumulation of amyloid β (Aβ) and neurofibrillary tangles. Oxidative stress and inflammation are considered to play an important role in the development and progression of AD. However, the extent to which these events contribute to the Aβ pathologies remains unclear. We performed inter-species comparative gene expression profiling between AD patient brains and the App NL-G-F/NL-G-F and 3xTg-AD-H mouse models. Genes commonly altered in App NL-G-F/NL-G-F and human AD cortices correlated with the inflammatory response or immunological disease. Among them, expression of AD-related genes (C4a/C4b, Cd74, Ctss, Gfap, Nfe2l2, Phyhd1, S100b, Tf, Tgfbr2, and Vim) was increased in the App NL-G-F/NL-G-F cortex as Aβ amyloidosis progressed with exacerbated gliosis, while genes commonly altered in the 3xTg-AD-H and human AD cortices correlated with neurological disease. The App NL-G-F/NL-G-F cortex also had altere...
Acta neuropathologica, 2002
Amyloid-beta (Abeta) deposition in cerebral blood vessel walls is one of the key features of Alzheimer's disease (AD). Abeta(1-40) carrying the "Dutch" mutation (DAbeta(1-40)) induces rapid degeneration of cultured human brain pericytes (HBP). To study the mechanisms of this Abeta-induced toxicity, a comparative cDNA expression array was performed to detect differential gene expression of Abeta-treated versus untreated HBP. Messenger RNA expression of leukemia inhibitory factor (LIF) and insulin-like growth factor binding protein 3 (IGFBP-3) was increased in DAbeta(1-40)-treated HBP, whereas early growth response factor-1 (Egr-1) expression was decreased. Corresponding protein expression was investigated in AD and control brains. In all AD cases examined, LIF expression was observed in senile plaques and cerebral amyloid angiopathy, whereas IGFBP-3 expression in these lesions was only observed in a subset of cases. LIF and IGFBP-3 were also expressed in neurofibrillary...
Brain site-specific gene expression analysis in Alzheimer’s disease patients
Background: Alzheimer's disease (AD) is an age-related neurodegenerative disorder that is characterized by a progressive loss of higher cognitive functions. The brain of an individual with AD exhibits extracellular senile plaques (SPs) of aggregated amyloid-beta peptide (Abeta) and intracellular neurofibrillary tangles (NFTs). Given the critical role of neuronal transport of both proteins and organelles, it is not surprising that perturbation of microtubule-based transport may play a major role in the pathogenesis of AD. MATERIALS AND METHODS: We used the cDNA subtraction methodology and in vitro neural cell culture analyses to study the meaning of the brain site-specific gene expression pattern in cerebral tissue obtained from AD patients and also from control subjects at autopsy. RESULTS: We observed that cytoskeleton-associated proteins were down-regulated in AD subjects. We also noted an altered expression of the microtubule-associated protein 1B (MAP1B), the heat-shock protein (HSP)-90 (a key chaperone molecule), the tripartite motif-containing proteins (TRIM)-32/37 (an anti apoptotic enzyme with ubiquitin-protein ligase activity) and the Reticulon-3 (a modulator of the amyloid-precursor-protein (APP) cleavage) in AD brains. Additional molecular- and cell-biological studies revealed that small interfering RNA (siRNA)-mediated down-regulation of MAP1B expression leads to neuronal cell death in vitro. CONCLUSION: Altered expression of MAP1B, HSP90, TRIM32/37 and Reticulon-3 provides new clues by which the ubiquitin-proteasome-, the protein-chaperon- and the APP-processing systems are disturbed in AD, thus, leading to neuritic amyloid plaques and neurofibrillary tangles.
Altered gene expression and neuropathology in Alzheimer's disease
Neurobiology of Aging, 2006
In their review article published in this issue of Neurobiology of Aging, Reddy and McWeeney provide an overview on the neuropathology of Alzheimer's disease (AD), genes related to AD, transgenic animal models of AD, and results from studies which have focused on alterations in gene expression in AD, performed both on postmortem brains from patients with AD and controls as well as on transgenic mouse models of this disease. Their major conclusion is that findings from studies carried out to date on alterations in gene expression in AD are still limited in terms of their utility in treating AD patients and in developing early methods of detection. We generally agree with most of the ideas and trajectories of Reddy and McWeeney . However, we would like to draw attention to the following issues.
Down-regulation of cyclin D2 in amyloid β toxicity, inflammation, and Alzheimer’s disease
PLOS ONE, 2021
In the current study, we analyzed the effects of the systemic inflammatory response (SIR) and amyloid β (Aβ) peptide on the expression of genes encoding cyclins and cyclin-dependent kinase (Cdk) in: (i) PC12 cells overexpressing human beta amyloid precursor protein (βAPP), wild-type (APPwt-PC12), or carrying the Swedish mutantion (APPsw-PC12); (ii) the murine hippocampus during SIR; and (iii) Alzheimer's disease (AD) brain. In APPwt-PC12 expression of cyclin D2 (cD2) was exclusively reduced, and in APPsw-PC12 cyclins cD2 and also cA1 were down-regulated, but cA2, cB1, cB2, and cE1 were up-regulated. In the SIR cD2, cB2, cE1 were found to be significantly down-regulated and cD3, Cdk5, and Cdk7 were significantly up-regulated. Cyclin cD2 was also found to be down-regulated in AD neocortex and hippocampus. Our novel data indicate that Aβ peptide and inflammation both significantly decreased the expression of cD2, suggesting that Aβ peptides may also contribute to downregulation of cD2 in AD brain.