Pharmacogenomics of Alzheimer's disease

Takeda, Masatoshi; Martínez, Rocío; Kudo, Takashi; Tanaka, Toshihisa; Okochi, Masayasu; Tagami, Shinji; Morita, Takashi; Hashimoto, Ryota; Cacabelos, Ramón

doi:10.1111/j.1758-5872.2011.00113.x

Cited by 4 publications

(4 citation statements)

References 39 publications

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“…Both Apoe and Gap43 were downregulated in oligodendrocytes on DEX addition. APOE has a major role in lipid metabolism, 39 but its role in the genesis of lipid rich myelin sheaths in the CNS is currently unclear. Gap43 is expressed in immature oligodendrocytes but down regulated during maturation; 40 although we did not detect morphological alterations in CS treated oligodendrocytes, we cannot currently rule out alterations in their engagement with axons.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

Identifying the Cellular Targets of Drug Action in the Central Nervous System Following Corticosteroid Therapy

Jenkins

Pickard

Khong

et al. 2013

ACS Chem. Neurosci.

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Corticosteroid (CS) therapy is used widely in the treatment of a range of pathologies, but can delay production of myelin, the insulating sheath around central nervous system nerve fibers. The cellular targets of CS action are not fully understood, that is, "direct" action on cells involved in myelin genesis [oligodendrocytes and their progenitors the oligodendrocyte precursor cells (OPCs)] versus "indirect" action on other neural cells. We evaluated the effects of the widely used CS dexamethasone (DEX) on purified OPCs and oligodendrocytes, employing complementary histological and transcriptional analyses. Histological assessments showed no DEX effects on OPC proliferation or oligodendrocyte genesis/maturation (key processes underpinning myelin genesis). Immunostaining and RT-PCR analyses show that both cell types express glucocorticoid receptor (GR; the target for DEX action), ruling out receptor expression as a causal factor in the lack of DEX-responsiveness. GRs function as ligand-activated transcription factors, so we simultaneously analyzed DEX-induced transcriptional responses using microarray analyses; these substantiated the histological findings, with limited gene expression changes in DEX-treated OPCs and oligodendrocytes. With identical treatment, microglial cells showed profound and global changes post-DEX addition; an unexpected finding was the identification of the transcription factor Olig1, a master regulator of myelination, as a DEX responsive gene in microglia. Our data indicate that CS-induced myelination delays are unlikely to be due to direct drug action on OPCs or oligodendrocytes, and may occur secondary to alterations in other neural cells, such as the immune component. To the best of our knowledge, this is the first comparative molecular and cellular analysis of CS effects in glial cells, to investigate the targets of this major class of anti-inflammatory drugs as a basis for myelination deficits.

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Section: ■ Results and Discussionmentioning

confidence: 99%

Identifying the Cellular Targets of Drug Action in the Central Nervous System Following Corticosteroid Therapy

Jenkins

Pickard

Khong

et al. 2013

ACS Chem. Neurosci.

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“…As the protein component of lipoproteins, apoE is a major lipid transport protein and the only apolipoprotein expressed in the brain, where it is expressed primarily by astrocytes. Thus, apoE is crucial for brain lipid homeostasis, as cholesterol and phospholipids are required for neuronal growth, repair and synaptogenesis (14)(15)(16). In humans, apoE is a 299 amino acid protein that has three naturally occurring isoforms that differ by a single amino acid change: apoE2 (Cys 112,158 ), apoE3 (Cys 112 Arg 158 ), and apoE4 (Arg 112,158 ) (16).…”

Section: Introductionmentioning

confidence: 99%

APOE4 Induces Site-Specific Tau Phosphorylation Through Calpain-CDK5 Signaling Pathway in EFAD-Tg Mice

Zhou¹,

Huang²,

Collins³

et al. 2016

CAR

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APOE4 is the greatest genetic risk factor for Alzheimer's disease (AD), particularly associated with increased levels of amyloid-β (Aβ) and amyloid deposition. However, it remains unclear whether APOE4 is associated with greater tau phosphorylation and neurofibrillary tangle formation, a hallmark of AD leading to structural disruption of the neuronal cytoskeleton. The current study used 3 and 7 month old EFAD mice, which express human APOE and over-express specifically human Aβ42 via 5 familial-AD (FAD) mutations, to investigate APOE genotype-specific effects on site-specific tau phosphorylation. The results reveal that AD-like site-specific tau phosphorylation was increased in E4FAD mice, accompanied by disrupted cortical neuronal morphology, compared to E3FAD mice. Further analysis demonstrated that the levels of CDK5, its regulatory subunits (p35 and p25) and calpain (including calpain1 and calpain2), but not GSK3β, were significantly increased in E4FAD mice compared to E3FAD mice. These results suggest that the APOE4 genotype contributes to increased site-specific tau phosphorylation via activation of the calpain-CDK5 signaling pathway.

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“…Carriers of ApoE4 allele have higher levels of cholesterol, owing to more efficient absorption from the intestine, and, consequently, face a higher risk of hypertension and of cardiovascular and Alzheimer's diseases [13][14][15][16]. By contrast, the ApoE3 allele is related to lower levels of cholesterol and a lower disease risk.…”

Section: Introductionmentioning

confidence: 99%

Apolipoprotein E ( ApoE ) polymorphism is related to differences in potential fertility in women: a case of antagonistic pleiotropy?

et al. 2015

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The alleles that are detrimental to health, especially in older age, are thought to persist in populations because they also confer some benefits for individuals (through antagonistic pleiotropy). The ApoE4 allele at the ApoE locus, encoding apolipoprotein E (ApoE), significantly increases risk of poor health, and yet it is present in many populations at relatively high frequencies. Why has it not been replaced by natural selection with the health-beneficial ApoE3 allele? ApoE is a major supplier of cholesterol precursor for the production of ovarian oestrogen and progesterone, thus ApoE has been suggested as the potential candidate gene that may cause variation in reproductive performance. Our results support this hypothesis showing that in 117 regularly menstruating women those with genotypes with at least one ApoE4 allele had significantly higher levels of mean luteal progesterone (144.21 pmol l 21 ) than women with genotypes without ApoE4 (120.49 pmol l 21 ), which indicates higher potential fertility. The hormonal profiles were based on daily data for entire menstrual cycles. We suggest that the finding of higher progesterone in women with ApoE4 allele could provide first strong evidence for an evolutionary mechanism of maintaining the ancestral and health-worsening ApoE4 allele in human populations.

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Pharmacogenomics of Alzheimer's disease

Cited by 4 publications

References 39 publications

Identifying the Cellular Targets of Drug Action in the Central Nervous System Following Corticosteroid Therapy

Identifying the Cellular Targets of Drug Action in the Central Nervous System Following Corticosteroid Therapy

APOE4 Induces Site-Specific Tau Phosphorylation Through Calpain-CDK5 Signaling Pathway in EFAD-Tg Mice

Apolipoprotein E ( ApoE ) polymorphism is related to differences in potential fertility in women: a case of antagonistic pleiotropy?

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