Altered expression of genes for amyloid and cytoskeletal proteins in alzheimer cortex

Clark, Arthur W.; Krekoski, Craig A.; Parhad, Irma M.; Liston, Dane; Julien, Jean‐Pierre; Hoar, David I.

doi:10.1002/ana.410250404

Cited by 70 publications

(25 citation statements)

References 35 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…For example, a depleted NF content might render other neuronal populations more susceptible to excitotoxic or other insults thought to be involved in human neurodegenerative diseases. Reports have described decreased levels of NF-L mRNA beyond that seen in normal aging in Alzheimer's disease brain (McLachlan et al, 1988;Clark et al, 1989;Somerville et al, 1991;Robinson et al, 1994). Future studies in these animals promise to yield additional insights into the mechanisms that underlie this degenerative process as well as lead to further clarification of the normal function of NFs and their role in neurodegenerative diseases.…”

Section: Discussionmentioning

confidence: 98%

Age-related Atrophy of Motor Axons in Mice Deficient in the Mid-sized Neurofilament Subunit

Elder¹

1999

The Journal of Cell Biology

View full text Add to dashboard Cite

Abstract. Neurofilaments are central determinants of the diameter of myelinated axons. It is less clear whether neurofilaments serve other functional roles such as maintaining the structural integrity of axons over time. Here we show that an age-dependent axonal atrophy develops in the lumbar ventral roots of mice with a null mutation in the mid-sized neurofilament subunit (NF-M) but not in animals with a null mutation in the heavy neurofilament subunit (NF-H). Mice with null mutations in both genes develop atrophy in ventral and dorsal roots as well as a hind limb paralysis with aging. The atrophic process is not accompanied by significant axonal loss or anterior horn cell pathology. In the NF-M-null mutant atrophic ventral root, axons show an age-related depletion of neurofilaments and an increased ratio of microtubules/neurofilaments. By contrast, the preserved dorsal root axons of NF-M-null mutant animals do not show a similar depletion of neurofilaments. Thus, the lack of an NF-M subunit renders some axons selectively vulnerable to an age-dependent atrophic process. These studies argue that neurofilaments are necessary for the structural maintenance of some populations of axons during aging and that the NF-M subunit is especially critical.

show abstract

Section: Discussionmentioning

confidence: 98%

Age-related Atrophy of Motor Axons in Mice Deficient in the Mid-sized Neurofilament Subunit

Elder¹

1999

The Journal of Cell Biology

View full text Add to dashboard Cite

show abstract

“…First, there are differences between Alzheimer disease patients and controls in the levels of APP mRNAs in certain brain regions (19,23,(26)(27)(28)(29)(30). Second, the difference in the level of APP mRNAs between trisomy 21 Down-syndrome patients and controls having two chromosomes 21 was higher than the expected 3:2 ratio (9).…”

Section: Introductionmentioning

confidence: 95%

Interleukin 1 regulates synthesis of amyloid beta-protein precursor mRNA in human endothelial cells.

Goldgaber

Harris

Hla

et al. 1989

Proc. Natl. Acad. Sci. U.S.A.

510

237

View full text Add to dashboard Cite

We have analyzed the modulation of amyloid (3-protein precursor (APP) gene expression in human umbilical vein endothelial cells (HUVEC). The level of the APP mRNA transcripts increased as HUVEC reached confluency. In confluent culture the half-life of the APP mRNA was 4 hr. Treatment of the cells with human recombinant interleukin 1 (IL-1), phorbol 12-myristate 13-acetate, or heparin-binding growth factor 1 enhanced the expression of APP gene in these cells, but calcium ionophore A23187 and dexamethasone did not. The protein kinase C inhibitor 1-(isoquinolinsulfonyl)-2-methylpiperazine (H7) inhibited IL-1-mediated increase of the level of APP transcripts. To map IL-1-responsive elements of the APP promoter, truncated portions of the APP promoter were fused to the human growth hormone reporter gene. The recombinant plasmids were transfected into mouse neuroblastoma cells, and the cell medium was assayed for the human growth hormone. A 180-base-pair region of the APP promoter located between position -485 and -305 upstream from the transcription start site was necessary for IL-1-mediated induction of the reporter gene. This region contains the upstream transcription factor AP-1 binding site. These results suggest that IL-1 upregulates APP gene expression in HUVEC through a pathway mediated by protein kinase C, utilizing the upstream AP-1 binding site of the APP promoter.The amyloid A3-protein precursor (APP) gene codes for a family of proteins, each containing a 42-amino acid fragment called amyloid 3 or A4 protein, that is found in brains and the cerebrovasculature of Alzheimer disease, Down syndrome, hereditary cerebral hemorrhage (Dutch type), and aging (1)(2)(3)(4)(5). The APP gene is transcriptionally active in a variety of tissues, highly conserved in evolution, maps to human chromosome 21 (6-10), and probably has no mutations associated with Alzheimer disease (11, 12). Transcripts containing three similar but nonidentical open reading frames have been identified (13)(14)(15)(16)(17). In situ hybridization studies show a very complex pattern of the APP gene expression in brain (18-23).Different levels of APP mRNAs were detected in neurons, some glial cells, and cells that compose blood vessels, presumably some endothelial cells (23). The detection of APP mRNA in these cells strengthens the possibility that at least one form of amyloid 83-protein-cerebrovascular-could originate locally from blood vessels (24, 25).The importance ofunderstanding the regulation ofthe APP gene is underscored by two observations. First, there are differences between Alzheimer disease patients and controls in the levels of APP mRNAs in certain brain regions (19,23,(26)(27)(28)(29)(30). Second, the difference in the level of APP mRNAs between trisomy 21 Down-syndrome patients and controls having two chromosomes 21 was higher than the expected 3:2 ratio (9). In the absence of structural mutations, aberrant levels of the precursor protein may contribute to pathology. These observations suggest that there is aberrant regulation...

show abstract

“…The significant reduction in tubulin (44) mentioned earlier may be related to, and perhaps precede, neuronal loss. In a Northern analysis of levels of tubulin mRNA in AD cortex, the signal intensity for tubulin was 47% of control values (83). This decrease may be due to loss of neurons.…”

Section: Introductionmentioning

confidence: 86%

Hypothesis: microtubules, a key to Alzheimer disease.

Matsuyama¹,

Jarvik²

1989

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

Alzheimer disease (AD) is a clinicopathologic syndrome of unknown etiology with numerous abnormalities in neuronal and nonneuronal cells. A review of the literature suggests that a common basic intracellular defect may underlie many of the reported abnormalities. We hypothesize impairment of the microtubule (MT) system as one explanation for the pathogenesis of AD. Evidence in support of the hypothesis includes the following: MTs are ubiquitous and vital cell components, unequally distributed, with the highest concentration in the brain; various abnormalities, including the key neuropathologic lesions, can be explained by impairments of the MT system; and experiments utilizing pharmacologic agents known to disrupt MTs have reproduced certain abnormalities observed in AD. The hypothesis provides a framework for systematic investigations of MTs at the cellular and molecular levels as well as the basis for in vivo diagnostic tests for AD.

show abstract

Altered expression of genes for amyloid and cytoskeletal proteins in alzheimer cortex

Cited by 70 publications

References 35 publications

Age-related Atrophy of Motor Axons in Mice Deficient in the Mid-sized Neurofilament Subunit

Age-related Atrophy of Motor Axons in Mice Deficient in the Mid-sized Neurofilament Subunit

Interleukin 1 regulates synthesis of amyloid beta-protein precursor mRNA in human endothelial cells.

Hypothesis: microtubules, a key to Alzheimer disease.

Contact Info

Product

Resources

About