Neurofilament light gene deletion exacerbates amyloid, dystrophic neurite, and synaptic pathology in the APP/PS1 transgenic model of Alzheimer's disease

Fernández-Martos, Carmen M.; King, Anna E.; Atkinson, Rachel A.K.; Woodhouse, Adele; Vickers, James C.

doi:10.1016/j.neurobiolaging.2015.07.003

Cited by 29 publications

(37 citation statements)

References 67 publications

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“…Therefore, TRIM2 seemed to play crucial roles in this modulating process. However, it is reported that mutation or loss of function of TRIM2 will lead to the accumulation of NF-L resulting in progressive neurodegeneration [19,27], while NF-L deficiency significantly increases neocortical dystrophic neuritis pathology and Aβ deposition as well as synapse vulnerability [46]. Therefore, maintaining expressive balance of TRIM2 is important.…”

Section: Discussionmentioning

confidence: 99%

MicroRNA-181c Ameliorates Cognitive Impairment Induced by Chronic Cerebral Hypoperfusion in Rats

Chen

Min

et al. 2016

Mol Neurobiol

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Chronic cerebral hypoperfusion (CCH) characterized by global cerebral ischemia is an important risk factor contributing to the development of dementia. MicroRNAs (miRNAs) play important roles in the cellular adaptation to long-term ischemia/hypoxia by turning off or on the expression of target genes. MiR-181c is widely expressed in the nervous system, and tripartite motif 2 (TRIM2) is one of its target genes. In this work, we had identified that progressive spatial memory deficiency was induced in the bilateral common carotid artery occlusion (2-VO) rat models. Meanwhile, inhibition of miR-181c expression and upregulation of TRIM2 in the hippocampus of 2-VO rats were found accompanying with reduction in the dendritic branching and dendrite spine density of the hippocampal neurons. Viral vector-mediated miR-181c delivery might improve the cognitive deficiency via TRIM2 on neurofilament light (NF-L) ubiquitination resulting in remodeling of the hippocampal neurons as well as increase in N-methyl-D-aspartate receptor 1 (NR1) subunit cell surface expression. Meanwhile, miR-181c might rescue the cellular activity from ischemia/hypoxia. These results indicated a novel miRNA-mediated mechanism involving miR-181c and TRIM2 in the cognitive impairment induced by CCH and provided a rationale for the development of miRNA-based strategies for prevention of dementia.

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Section: Discussionmentioning

confidence: 99%

MicroRNA-181c Ameliorates Cognitive Impairment Induced by Chronic Cerebral Hypoperfusion in Rats

Chen

Min

et al. 2016

Mol Neurobiol

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“…Previous studies have used this experimental approach to investigate the role of NFs in different transgenic mouse models of neurodegenerative disease however, the resulting phenotype alterations have been disparate [32,33]. Interestingly, tau transgenic mice (T44) showed a delay in disease onset [33] whereas APP/PS1 transgenic mice displayed increased levels of pathology and synaptic vulnerability when NFL was absent [32]. In the present study, we observed no major differences in the onset of disease or αS pathology in human A53T αS transgenic (M83) mice [40] with or without NFL following αS fibril seeding from intramuscular injection.…”

Section: Discussionmentioning

confidence: 99%

“…The involvement of NFs in neurodegeneration is an active area of research and has been investigated by breeding transgenic mouse models of AD and tauopathy onto an NFL null background in order to assess the contribution of NFs to the pathogenesis of disease in these particular models [32,33]. Ishihara and colleagues observed delayed development of the typical behavioral phenotype and reduced pathology in mice transgenic for human tau (T44 mice)[34] when they lacked NFs compared toT44 mice with NFs [33] suggesting that NFs, at least in part, contribute to the onset of tauopathy in these mice.…”

Section: Introduction1mentioning

confidence: 99%

“…Ishihara and colleagues observed delayed development of the typical behavioral phenotype and reduced pathology in mice transgenic for human tau (T44 mice)[34] when they lacked NFs compared toT44 mice with NFs [33] suggesting that NFs, at least in part, contribute to the onset of tauopathy in these mice. However, Fernandez et al observed a worsening of the pathological phenotype in their APP/PS1 (APPswe/PSEN1dE9) transgenic mice on an NFL null background [32,35]. They detected an increase in cortical amyloid-β (Aβ) deposition and dystrophic neurite pathology along with increased synaptic vulnerability [32], which suggests that NFs may play a protective role in this mouse model.…”

Section: Introduction1mentioning

confidence: 99%

“…However, Fernandez et al observed a worsening of the pathological phenotype in their APP/PS1 (APPswe/PSEN1dE9) transgenic mice on an NFL null background [32,35]. They detected an increase in cortical amyloid-β (Aβ) deposition and dystrophic neurite pathology along with increased synaptic vulnerability [32], which suggests that NFs may play a protective role in this mouse model. These two studies show opposing effects of the deficiency of NFL, and therefore NFs, on the disease phenotype in their models of neurodegeneration.…”

Section: Introduction1mentioning

confidence: 99%

See 2 more Smart Citations

Prion-like transmission of α-synuclein pathology in the context of an NFL null background

Rutherford

Brooks

Riffe

et al. 2017

Neuroscience Letters

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Neurofilaments are a major component of the axonal cytoskeleton in neurons and have been implicated in a number of neurodegenerative diseases due to their presence within characteristic pathological inclusions. Their contribution to these diseases are not yet fully understood, but previous studies investigated the effects of ablating the obligate subunit of neurofilaments, low molecular mass neurofilament subunit (NFL), on disease phenotypes in transgenic mouse models of Alzheimer’s disease and tauopathy. Here, we tested the effects of ablating NFL in α-synuclein M83 transgenic mice expressing the human pathogenic A53T mutation, by breeding them onto an NFL null background. The induction and spread of α-synuclein inclusion pathology was triggered by the injection of preformed α-synuclein fibrils into the gastrocnemius muscle or hippocampus in M83 versus M83/NFL null mice. We observed no difference in the post-injection time to motor-impairment and paralysis endpoint or amount and distribution of α-synuclein inclusion pathology in the muscle injected M83 and M83/NFL null mice. Hippocampal injected M83/NFL null mice displayed subtle region-specific differences in the amount of α-synuclein inclusions however, pathology was observed in the same regions as the M83 mice. Overall, we observed only minor differences in the induction and transmission of α-synuclein pathology in these induced models of synucleinopathy in the presence or absence of NFL. This suggests that NFL and neurofilaments do not play a major role in influencing the induction and transmission of α-synuclein aggregation.

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Cerebrospinal fluid biomarkers for understanding multiple aspects of Alzheimer’s disease pathogenesis

Dhiman

Blennow

Zetterberg

et al. 2019

Cell. Mol. Life Sci.

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Alzheimer's disease (AD) is a multifactorial age-related brain disease. Numerous pathological events run forth in the brain leading to AD. There is an initial long, dormant phase before the clinical symptoms become evident. There is a need to diagnose the disease at the preclinical stage since therapeutic interventions are most likely to be effective if initiated early.Undoubtedly, the core cerebrospinal fluid (CSF) biomarkers have a good diagnostic accuracy and have been used in clinical trials as end point measures. However, looking into the multifactorial nature of AD and the overlapping pathology with other forms of dementia, it is important to integrate the core CSF biomarkers with a broader panel of other biomarkers. These include proteins reflecting different aspects of pathology such as neurodegeneration, neuroinflammation and synaptic dysfunction. The combination of biomarkers would not only aid in preclinical diagnosis, but would also help in identifying early brain changes during the onset of disease. Successful treatment strategies can be devised by understanding the contribution of these markers in different aspects of disease pathogenesis.

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Neurofilament light gene deletion exacerbates amyloid, dystrophic neurite, and synaptic pathology in the APP/PS1 transgenic model of Alzheimer's disease

Cited by 29 publications

References 67 publications

MicroRNA-181c Ameliorates Cognitive Impairment Induced by Chronic Cerebral Hypoperfusion in Rats

MicroRNA-181c Ameliorates Cognitive Impairment Induced by Chronic Cerebral Hypoperfusion in Rats

Prion-like transmission of α-synuclein pathology in the context of an NFL null background

Cerebrospinal fluid biomarkers for understanding multiple aspects of Alzheimer’s disease pathogenesis

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