Axonal degeneration promotes abnormal accumulation of amyloid β-protein in ascending gracile tract of gracile axonal dystrophy (GAD) mouse

Ichihara, Nobutsune; Wu, Jiawen; Chui, De Hua; Yamazaki, Kazuto; Wakabayashi, Tsuneo; Kikuchi, Tateki

doi:10.1016/0006-8993(95)00729-a

Cited by 68 publications

(43 citation statements)

References 32 publications

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“…The development of amyloid plaques in the brain as a result of amyloid deposition is a phenomenon seldom found in ALS [38]. The presence of axonal degeneration is supported by studies of the gracile axonal dystrophy mouse, in which increased amyloid precursor protein (APP) immunoreactivity is detected in degenerating neurons after 4 weeks of age, followed by an increase in ß-amyloid immunoreactivity after 9 weeks [37]. In support of this is also the finding that increased immunoreactivity of APP has been found in the perikarya and in some proximal axonal swellings in the anterior horn cells in ALS [39].…”

Section: Discussionmentioning

confidence: 57%

“…The finding that CSF-Aß42 was decreased in ALS suggests that this change is not specific for AD but reflects a more general change in the metabolism of Aß42. It is probably a reflection of the mismetabolism of ß-amyloid that occurs in neurodegeneration and that may be related either to amyloid deposition [13,36] or to axonal degeneration [37]. The development of amyloid plaques in the brain as a result of amyloid deposition is a phenomenon seldom found in ALS [38].…”

Section: Discussionmentioning

confidence: 99%

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Decreased CSF-β-Amyloid 42 in Alzheimer’s Disease and Amyotrophic Lateral Sclerosis May Reflect Mismetabolism of β-Amyloid Induced by Disparate Mechanisms

Sjögren

Davidsson

Wallin

et al. 2002

Dement Geriatr Cogn Disord

133

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Both tau and β-amyloid 42 (Aβ42) have been implicated in Alzheimer’s disease (AD) and tau alone in frontotemporal dementia (FTD) and amyotrophic lateral sclerosis (ALS). These proteins can be measured in the cerebrospinal fluid (CSF); differences from normal CSF levels may reflect pathophysiological mechanisms. Using ELISAs, we investigated the levels of total CSF-tau (here referred to as tau), phosphorylated CSF-tau (phosphotau), and Aβ42 in patients with AD (n = 19), FTD (n = 14), ALS (n = 11) and Parkinson’s disease (PD; n = 15) and in age-matched controls (n = 17). Both CSF-tau and CSF-phosphotau were increased in AD compared with FTD (p < 0.001), ALS (p < 0.001), PD (p < 0.001) and controls (p < 0.001). CSF-Aβ42 was markedly decreased in AD and ALS (both p < 0.001) and slightly decreased in FTD (p < 0.01) and PD (p < 0.05) compared with controls. Using CSF-phosphotau may improve the differentiation of AD from FTD and ALS in clinical praxis. Furthermore, decreased CSF-Aβ42 levels may be common in neurodegenerative disorders possibly reflecting changes in the metabolism of β-amyloid or axonal degeneration.

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Section: Discussionmentioning

confidence: 57%

Section: Discussionmentioning

confidence: 99%

Decreased CSF-β-Amyloid 42 in Alzheimer’s Disease and Amyotrophic Lateral Sclerosis May Reflect Mismetabolism of β-Amyloid Induced by Disparate Mechanisms

Sjögren

Davidsson

Wallin

et al. 2002

Dement Geriatr Cogn Disord

133

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“…Much of the knowledge of the function of UCHL1 is from the gracile axonal dystrophy mouse, a naturally occurring mutant that lacks the UCHL1 protein due to a deletion of a genomic fragment that includes exons 7 and 8 (43). These mice develop neurodegenerative disease and inclusions within neuronal cells that are composed of ubiquitin and abnormal proteins (44). Under normal conditions, when proteins are tagged with ubiquitin, they are targeted for degradation within the cell.…”

Section: Discussionmentioning

confidence: 99%

Up-regulation of Expression of the Ubiquitin Carboxyl-Terminal Hydrolase L1 Gene in Human Airway Epithelium of Cigarette Smokers

Carolan¹,

Heguy²,

Harvey

et al. 2006

Cancer Research

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Neuroendocrine differentiation is a common feature of lung cancer and increased numbers of neuroendocrine cells and their peptides have been described in chronic smokers. To understand the effects of cigarette smoking on the gene expression profile of neuroendocrine cells, microarray analysis with TaqMan confirmation was used to assess airway epithelial samples obtained by fiberoptic bronchoscopy from 81 individuals [normal nonsmokers, normal smokers, smokers with early chronic obstructive lung disease (COPD), and smokers with established COPD]. Of 11 genes considered to be neuroendocrine cell specific, only ubiquitin carboxyl-terminal hydrolase L1 (UCHL1), a member of the ubiquitin proteasome pathway, was consistently up-regulated in smokers compared with nonsmokers. Up-regulation of UCHL1 at the protein level was observed with immunohistochemical analysis of bronchial biopsies of smokers compared with nonsmokers. UCHL1 expression was evident only in neuroendocrine cells of the airway epithelium in nonsmokers; however, UCHL1 was also expressed in ciliated epithelial cells in smokers. This observation may add further weight to recent observations that ciliated cells are capable of transdifferentiating to other airway epithelial cells. In the context that UCHL1 is involved in the degradation of unwanted, misfolded, or damaged proteins within the cell and is overexpressed in >50% of lung cancers, its overexpression in chronic smokers may represent an early event in the complex transformation from normal epithelium to overt malignancy. (Cancer Res 2006; 66(22): 10729-40)

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“…112,113 In line with the high turnover, rapid anterograde transport, and processing of APP in distal compartments, [114][115][116] genetically induced fibre tract degeneration in the gracile axonal dystrophy mouse provokes rapid axonal accumulation of APP and Aβ. 117 Moreover, disruption of axonal and dendritic transport following impaired lysosomal proteolysis is accompanied by increased levels of C-terminally cleaved APP fragments, 118 which indicates that a combination of increased synthesis and impaired axonal transport of APP induces its rapid accumulation in neurites with subsequent aberrant cleavage. Notably, however, APP was recently shown to be required for maintenance of distal synaptic connections in APP/APLP2 knockout mice.…”

Section: Inflammation and Cellular Stressmentioning

confidence: 99%

Deciphering the mechanism underlying late-onset Alzheimer disease

2012

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Despite tremendous investments in understanding the complex molecular mechanisms underlying Alzheimer disease (AD), recent clinical trials have failed to show efficacy. A potential problem underlying these failures is the assumption that the molecular mechanism mediating the genetically determined form of the disease is identical to the one resulting in late-onset AD. Here, we integrate experimental evidence outside the 'spotlight' of the genetic drivers of amyloid-(A) generation published during the past two decades, and present a mechanistic explanation for the pathophysiological changes that characterize late-onset AD. We propose that chronic inflammatory conditions cause dysregulation of mechanisms to clear misfolded or damaged neuronal proteins that accumulate with age, and concomitantly lead to tau-associated impairments of axonal integrity and transport. Such changes have several neuropathological consequences: focal accumulation of mitochondria, resulting in metabolic impairments; induction of axonal swelling and leakage, followed by destabilization of synaptic contacts; deposition of amyloid precursor protein in swollen neurites, and generation of aggregation-prone peptides; further tau hyperphosphorylation, ultimately resulting in neurofibrillary tangle formation and neuronal death. The proposed sequence of events provides a link between A and tau-related neuropathology, and underscores the concept that degenerating neurites represent a cause rather than a consequence of A accumulation in late-onset AD. Abstract | Despite tremendous investments in understanding the complex molecular mechanisms underlying Alzheimer disease (AD), recent clinical trials have failed to show efficacy. A potential problem underlying these failures is the assumption that the molecular mechanism mediating the genetically determined form of the disease is identical to the one resulting in late-onset AD. Here, we integrate experimental evidence outside the 'spotlight' of the genetic drivers of amyloid-β (Aβ) generation published during the past two decades, and present a mechanistic explanation for the pathophysiological changes that characterize late-onset AD. We propose that chronic inflammatory conditions cause dysregulation of mechanisms to clear misfolded or damaged neuronal proteins that accumulate with age, and concomitantly lead to tau-associated impairments of axonal integrity and transport. Such changes have several neuropathological consequences: focal accumulation of mitochondria, resulting in metabolic impairments; induction of axonal swelling and leakage, followed by destabilization of synaptic contacts; deposition of amyloid precursor protein in swollen neurites, and generation of aggregation-prone peptides; further tau hyperphosphorylation, ultimately resulting in neurofibrillary tangle formation and neuronal death. The proposed sequence of events provides a link between Aβ and tau-related neuropathology, and underscores the concept that degenerating neurites represent a cause rather than a consequence ...

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Axonal degeneration promotes abnormal accumulation of amyloid β-protein in ascending gracile tract of gracile axonal dystrophy (GAD) mouse

Cited by 68 publications

References 32 publications

Decreased CSF-β-Amyloid 42 in Alzheimer’s Disease and Amyotrophic Lateral Sclerosis May Reflect Mismetabolism of β-Amyloid Induced by Disparate Mechanisms

Decreased CSF-β-Amyloid 42 in Alzheimer’s Disease and Amyotrophic Lateral Sclerosis May Reflect Mismetabolism of β-Amyloid Induced by Disparate Mechanisms

Up-regulation of Expression of the Ubiquitin Carboxyl-Terminal Hydrolase L1 Gene in Human Airway Epithelium of Cigarette Smokers

Deciphering the mechanism underlying late-onset Alzheimer disease

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