Dystrophic Neurite Formation Associated with Age-Related β Amyloid Deposition in the Neocortex: Clues to the Genesis of Neurofibrillary Pathology

Vickers, James C.; Chin, Devika; Edwards, Ann Marie; Sampson, Viola; Harper, Clive; Morrison, John H.

doi:10.1006/exnr.1996.0133

Cited by 83 publications

(57 citation statements)

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“…Nevertheless, there are declines in levels of multiple neurotransmitters [7][8][9], as well as structural intracellular changes [10]. The latter include the accumulation of lipofuscin [11,12], the development of paired helical filaments [13,14], and the hyperphosphorylation of the microtubule-associated protein (MAP) [15,16]. In addition, there is an accumulation of reactive astrocytes and microglia [17], as well as structural deformities in myelin-forming oligodendrocytes [6].…”

Section: Introductionmentioning

confidence: 99%

Temporal Dynamics of Degenerative and Regenerative Events Associated with Cerebral Ischemia in Aged Rats

Badan

Platt²,

Kessler

et al. 2003

Gerontology

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Background and Purpose: The age-related decline in plasticity of the brain may be one factor underlying the poor functional recovery after stroke. In the present work we tested the hypothesis that the attenuation of neural plasticity could be the result of an age-related reduction in the upregulation of factors promoting brain plasticity (microtubule-associated protein 1B [MAP1B], β-amyloid precursor protein [βAPP]), and an age-related increase in glial reactivity and the accumulation of Aβ, a proteolytic cleavage product of βAPP with neurotoxic properties. Methods: Focal cerebral ischemia was produced by reversible occlusion of the right middle cerebral artery in 3- and 20-month-old male Sprague-Dawley rats. The functional outcome was assessed in neurobehavioral tests 3, 7, 14 and 28 days after surgery. At the indicated time points, brains were removed and immunostained for glial cells. Aβ, as well as the markers of brain plasticity, βAPP and MAP1B. Results: Histologically, in young rats there was a gradual activation of both microglia and astrocytes that peaked by days 14–28 with the formation of a glial scar. In contrast, aged rats showed an accelerated astrocytic and microglial reaction that peaked in the first week after stroke. The expression patterns of a growth-associated phenotype of βAPP as well as with MAP1B accumulation in varicosities along axons in cortical areas affected by stroke peaked between days 14 and 28 in young animals. In aged rats their expression was both delayed (28 days) and reduced. In addition the carboxy terminal fragment of βAPP steadily accumulated over time and reached a maximum by day 14 in aged rats as compared to 28 days in young rats. Conclusions: These results suggest that a temporally anomalous gliotic reaction to cerebral ischemia in aged rats in conjunction with a late and limited upregulation of neuronal plasticity proteins as well as a diminished neurogenesis potential lead to the prevalence of scar tissue that impedes functional recovery from stroke.

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Section: Introductionmentioning

confidence: 99%

Temporal Dynamics of Degenerative and Regenerative Events Associated with Cerebral Ischemia in Aged Rats

Badan

Platt²,

Kessler

et al. 2003

Gerontology

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“…Nevertheless, there are declines in the levels of multiple neurotransmitters [7][8][9], as well as structural intracellular changes [10]. The latter include the accumulation of lipofuscin [11,12], the development of paired helical filaments [13,14], and the hyperphos-Schmoll/Ramboiu/Platt/Herndon/Kessler/ Popa-Wagner phorylation of the microtubule-associated protein tau [15,16]. In addition, there are accumulations of reactive astrocytes and microglia [17], as well as structural deformations of myelin-forming oligodendrocytes [6].…”

Section: Introductionmentioning

confidence: 99%

Age Influences the Expression of GAP-43 in the Rat Hippocampus following Seizure

Schmoll

Ramboiu

Platt³

et al. 2005

Gerontology

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Background: Normal aging is associated with impairments in learning and memory and motor function. One viable hypothesis is that these changes reflect an age-related decrease in brain plasticity. Objective: The aim of the present study was to identify age-related changes in the time course of expression of the axonal growth associated protein 43 (GAP-43) in a rat model of brain plasticity. Methods: We examined by Northern blotting, in situ hybridization, and immunohistochemistry the effects of age on the time course of the expression GAP-43 following pentylenetetrazole-induced seizure in the hippocampus of 3-, 18-, and 28-month-old rats. Results: In this model of brain plasticity, young rats displayed a decrease in GAP-43 mRNA levels in CA1, CA3, and polymorphic regions, lasting from 10 h to 3 days after seizure. This was followed by recovery, with peak expression between days 10 and 20. The baseline levels of GAP-43 mRNA decreased with age, especially in the CA3 region. Despite lower baseline levels, middle-aged rats showed the same pattern of upregulation of GAP-43 mRNA expression as the young animals. Old rats showed only minimal upregulation, however, and this occurred only in the polymorphic layer. The level GAP-43 protein itself was higher in old control rats than in the other two control groups, a condition that was transiently reversed by seizure activity. Conclusions: Middle-aged rats are still capable of a sustained, though diminished, response to seizure activity, while old rats lose this ability. Disruption of the temporal and anatomical coordination of expression of GAP-43 may contribute to the general decline in brain plasticity with age.

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“…The earliest neurite changes associated with -amyloid plaque formation are identical to the reactive changes that follow in vitro and in vivo experimental injury (Masliah et al, 1993;Meller et al, 1994;DeWitt and Silver, 1996;Su et al, 1996;Vickers et al, 1996;Christman et al, 1997;King et al, 1997;2001;Dickson et al, 2000;in press;Chuckowree and Vickers, 2003). However, these experimental models of injury involve acute axonal injury, after which the damaged axons undergo reactive and regenerative changes and the injury is eventually resolved.…”

Section: A "Mass Effect" Variant Of the Amyloid Cascade Hypothesismentioning

confidence: 90%

“…Following findings that indicate that DNs, particularly in the earliest stages of AD, exhibit morphological and biochemical features that are identical to the axonal response to structural injury (Masliah et al, 1993;Meller et al, 1994;DeWitt and Silver, 1996;Su et al, 1996;Vickers et al, 1996;Christman et al, 1997;King et al, 1997;Nakamura et al, 1997;Dickson et al, 2000;King et al, 2001;Chuckowree and Vickers, 2003;Dickson et al, in press), our laboratory has proposed a variant of the amyloid cascade hypothesis (as previously reviewed in Vickers, 1997;King et al, 2000. Thus, we have proposed thatamyloid plaque formation, particularly the more dense plaques, causes physical deformation and injury to axons resulting in a cascade of cytoskeletal changes that lead to dystrophic neurite formation (King et al, 1997;Vickers, 1997;Dickson et al, 1999;in press;.…”

Section: A "Mass Effect" Variant Of the Amyloid Cascade Hypothesismentioning

confidence: 94%

“…As dense ß-amyloid plaques are considered to be relatively stable entities the physical trauma inflicted upon neurites in AD is chronically present and may interfere with the "normal" response to axonal injury. Thus, it is postulated that the chronic stimulation of the neuronal reaction to injury by ß-amyloid plaques, perhaps over many years, may cause changes in cytoskeletal elements such as the NFs and tau that lead to the formation of the abnormal insoluble filamentous structures, such as those in NFTs (Vickers et al, 1996;Dickson et al, 1999;Metsaars et al, 2003). To elaborate on the data leading to the formation of this mass effect hypothesis, the following sections of this review focus on the early neuronal changes that are specifically associated with plaque pathology, and how the stageing of neuronal alterations provides clues to the pattern of neural degeneration that underlies dementia.…”

Section: A "Mass Effect" Variant Of the Amyloid Cascade Hypothesismentioning

confidence: 99%

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Does β-amyloid plaque formation cause structural injury to neuronal processes?

et al. 2005

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The precise role of beta-amyloid plaque formation in the cascade of brain cell changes that lead to neurodegeneration and dementia in Alzheimer's disease has been unclear. Studies have indicated that neuronal processes surrounding and within plaques undergo a series of biochemical and morphological alterations. Morphological alterations include reactive, degenerative and sprouting-related 'dystrophic' neuritic structures, derived principally from axons, which involve specific changes in cytoskeletal proteins such as tau and NF triplet proteins. More compact and fibrous plaques are associated with more extensive neuritic pathology than non-fibrillar, diffuse beta-amyloid deposits. Cortical apical dendritic processes are either 'clipped' by plaque formation or are bent around more compact plaques. Examination of cases of 'pathological' brain ageing, which may represent a preclinical form of Alzheimer's disease, demonstrated that the earliest neuritic pathology associated with plaques was similar to the reactive changes that follow structural injury to axons. In vivo and in vitro experimental models of structural injury to axons produce identical reactive changes that subsequently lead to an attempt at regenerative sprouting by damaged axons. Thus, beta-amyloid plaque formation may cause structural injury to axons that is subsequently followed by an aberrant sprouting response that presages neurodegeneration and dementia. Identification of the key neuronal alterations underlying the pathology of Alzheimer's disease may provide new avenues for therapeutic intervention.

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Dystrophic Neurite Formation Associated with Age-Related β Amyloid Deposition in the Neocortex: Clues to the Genesis of Neurofibrillary Pathology

Cited by 83 publications

References 0 publications

Temporal Dynamics of Degenerative and Regenerative Events Associated with Cerebral Ischemia in Aged Rats

Temporal Dynamics of Degenerative and Regenerative Events Associated with Cerebral Ischemia in Aged Rats

Age Influences the Expression of GAP-43 in the Rat Hippocampus following Seizure

Does β-amyloid plaque formation cause structural injury to neuronal processes?

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