Localization and quantitation of 68 kDa neurofilament and superoxide dismutase-1 mRNA in alzheimer brains

Somerville, Martin J.; Percy, Maire E.; Bergeron, Catherine; Yoong, Larry K.K.; Grima, Etienne A.; McLachlan, Donald R.

doi:10.1016/0169-328x(91)90123-f

Cited by 50 publications

(21 citation statements)

References 21 publications

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“…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: 99%

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

Elder¹

1999

The Journal of Cell Biology

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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.

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Section: Discussionmentioning

confidence: 99%

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

Elder¹

1999

The Journal of Cell Biology

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“…The current study suggests that nonenzymatic glycation of PHF tau could contribute to its stabilization and also allow intracellular generation ofROIs, providing a molecular mechanism linking oxidant stress to the pathogenesis of AD (28)(29)(30)(31)(32). Aberrantly phosphorylated tau protein laid down in PHFs in enduring structures would be eminently susceptible to glycation because of its high lysine content and the high intraneuronal concentrations of aldose/aldose phosphate.…”

Section: Introduction Of Age-modifiedmentioning

confidence: 99%

“…These data do not exclude the possibility that other proteins associated with PHFs in neurofibrillary tangles may also be glycated to AGEs. The recognition that AGEs may be involved in disorders such as AD contributes to understanding their pathogenesis: since AGEs generate reactive oxygen intermediates, a mechanism is set up for inducing oxidant stress leading to neuronal dysfunction (28)(29)(30)(31)(32). This suggests possible strategies aimed at preventing AGE or ROI formation and its consequences for cellular integrity.…”

Section: Introduction Of Age-modifiedmentioning

confidence: 99%

Glycated tau protein in Alzheimer disease: a mechanism for induction of oxidant stress.

Yan

Chen

Schmidt

et al. 1994

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

518

246

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The stability of proteins that constitute the neurofibrillary tangles and senile plaques of Alzheimer disease suggests that they would be ideal substrates for nonenzymatic glycation, a process that occurs over long times, even at normal levels of glucose, ultimately resulting in the formation of advanced glycation end products (AGEs). AGE-modified proteins aggregate, and they generate reactive oxygen intermediates. Using monospecific antibody to AGEs, we have colocalized these AGEs with paired helical filament tau in neurofibrillary tangles in sporadic Alzheimer disease. Such neurons also exhibited evidence of oxidant stress: induction of malondialdehyde epitopes and heme oxygenase 1 antigen. AGErecombinant tau generated reactive oxygen intermediates and, when introduced into the cytoplasm of SH-SY5Y neuroblastoma cells, induced oxidant stress. We propose that in Alzheimer disease, AGEs in paired helical filament tau can induce oxidant stress, thereby promoting neuronal dysfunction.Proteins or lipids exposed to reducing sugars undergo nonenzymatic glycation and oxidation, initially with formation of Schiff bases and Amadori products on free amino groups, which ultimately undergo molecular rearrangement, to form irreversible advanced glycation end products (AGEs; refs. [1][2][3][4][5]. The AGEs are heterogeneous compounds of yellowbrown color and characteristic fluorescence (1-5). Accumulation of AGEs occurs on both intra-and extracellular structures, especially those whose turnover is prolonged. Although the formation of AGEs is accelerated in diabetes, it also occurs in normal aging. Proteins with many free amino groups (i.e., with high lysine content) are most readily glycated. AGE-modified proteins form crosslinks which result in aggregation and insolubility; they are also a continuing source ofpotentially damaging reactive oxygen intermediates (ROIs) and, when present extracellularly, interact with a distinct class of receptors (1-9). In cells, we have found that AGEs impart an oxidant stress manifested in endothelium by induction of heme oxygenase, activation of the transcription factor NF-KB, and formation of malondialdehyde epitopes of lipid peroxidation products (9). These perturbations, which result in changes in a spectrum of cellular properties (e.g., cell adherence, proliferation), were not accompanied by diminished cell viability (in short-term experiments), in keeping with a role for low levels of ROIs in signal transduction.The longstanding protein aggregates in Alzheimer disease (AD), such as paired helical filament (PHF) tau and amyloid .3protein (10)(11)(12) METHODS AGE ELISA, Immunoblotting, and Immunohistohemistry. AGE antigen was determined by using affinity-purified antibody to AGEs (9,13). This antibody selectively recognizes AGE forms of multiple proteins, but not the nonglycated counterparts (9) or formylated, maleylated, oxidized, or acetylated protein (9). To assay for AGE antigen (9), an ELISA was established by coating plates with brain homogenates/PHF tau (10-100 gg/ml) ove...

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“…It has been hypothesized that alterations in antioxidant systems, including SOD1, are implicated in neurodegenerative diseases (5,(11)(12)(13)(14)(15). In some cases of familial amyotrophic lateral sclerosis (FALS), mutations in SOD1 have been linked to disease (16)(17)(18), and at least two of these mutations can cause motor neuron disease when expressed in transgenic mice (ref.…”

mentioning

confidence: 99%

Superoxide dismutase is an abundant component in cell bodies, dendrites, and axons of motor neurons and in a subset of other neurons.

Pardo

Borchelt

et al. 1995

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

286

149

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Mutation in superoxide dismutase 1 (SODI), a Cu/Zn enzyme that removes oxygen radicals and protects against oxidative injury, has been implicated in some cases of familial amyotrophic lateral sclerosis (FALS). As a first approach to examining the mechanism(s) through which these mutations cause specific degeneration ofmotor neurons, we have used immunocytochemistry to identify the distribution of SODI in populations of cells in the peripheral and central nervous systems. In (02), yielding H202 and 02; subsequent removal of H202 is facilitated by catalase and glutathione peroxidase (2). Thus, SOD activity can protect against oxidative stress produced by oxygen radicals and may represent a first line of defense against oxidative damage mediated by oxygen radicals (1, 2).SODs are present in the central and peripheral nervous systems, but the cellular and intracellular distributions of SOD1 in neuronal populations are not well defined. Biochemical assays of SOD1 activity have not localized enzymatic activities to specific cells in the brain (3,4), and in situ hybridization and immunocytochemical studies have focused only on selected areas of the nervous system in either control (5-8) or diseased (9, 10) brain.It has been hypothesized that alterations in antioxidant systems, including SOD1, are implicated in neurodegenerative diseases (5,(11)(12)(13)(14)(15). In some cases of familial amyotrophic lateral sclerosis (FALS), mutations in SOD1 have been linked to disease (16)(17)(18), and at least two of these mutations can cause motor neuron disease when expressed in transgenic mice (ref. 19; unpublished observations). However, the mechanism(s) responsible for selective vulnerability to degeneration of motor neurons in FALS-linked SOD1 mutations is unknown. To identify events that lead to motor neuron death, it is critical to define the cellular distributions of SOD1 in the peripheral and central nervous systems. To this end, we have used protein blotting and immunocytochemistry at both light and electron microscopic levels to localize SOD1 in the mouse, nonhuman primate, and human nervous systems. MATERIALS AND METHODSGeneration and Characterization ofanti-SODI Antibody. A pentadecapeptide (CYDDLGDGGNEESTK) of which the C-terminal 13 amino acids correspond to residues 125-137 of mouse and human SOD1 was crosslinked to keyhole limpet hemocyanin (Pierce), emulsified in Freund's adjuvant, and used to immunize rabbits, as described (20) 954The publication costs of this article were defrayed in part by page charge payment. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. §1734 solely to indicate this fact.

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Localization and quantitation of 68 kDa neurofilament and superoxide dismutase-1 mRNA in alzheimer brains

Cited by 50 publications

References 21 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

Glycated tau protein in Alzheimer disease: a mechanism for induction of oxidant stress.

Superoxide dismutase is an abundant component in cell bodies, dendrites, and axons of motor neurons and in a subset of other neurons.

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