Neurofilament-Immunoreactive Neurons in Alzheimer's Disease and Dementia with Lewy Bodies

doi:10.1006/nbdi.2001.0469

Neurobiology of Disease

Volume 9, Issue 2, March 2002, Pages 249-257

https://doi.org/10.1006/nbdi.2001.0469 Get rights and content

Abstract

The cortical neurons thought to be selectively affected in dementia with Lewy bodies (DLB) are those containing nonphosphorylated 200-kDa neurofilament (NF) protein. As these neurons are largely spared in Alzheimer's disease (AD), DLB and AD may impact on different cortical neuronal populations. The present study quantifies the NF-containing neurons in frontal and temporal cortex of 8 AD, 8 DLB, and 8 control cases. Formalin-fixed paraffin-embedded tissue was immunohistochemically stained with antibodies against nonphosphorylated and phosphorylated NF. Immunoreactive neurons were quantified by areal fraction analysis and corrected for cortical volume. As expected, nonphosphorylated and phosphorylated NF accumulated in the pathological hallmarks of AD and DLB. However, rather than a decrease in NF-containing neurons, a doubling of this population was observed in DLB, compared with AD and controls. This increased number of cortical NF-containing neurons reveal novel widespread cortical changes, beyond those explained by Lewy body formation, that are specific for DLB.

References (46)

J-P. Brion et al.
Transgenic expression of the shortest human tau affects its compartmentalization and its phosphorylation as in the pretangle stage of Alzheimer's disease
Am. J. Pathol.
(1999)
K. Cullen et al.
Cell loss in the nucleus basalis is related to regional cortical atrophy in Alzheimer's disease
Neuroscience
(1997)
K.L. Double et al.
Topography of brain atrophy during normal aging and Alzheimer's disease
Neurobiol. Aging.
(1996)
T. Ishihara et al.
Age-dependent emergence and progression of a tauopathy in transgenic mice over-expressing the shortest human tau isoform
Neuron
(1999)
P. Klosen et al.
Perikaryal neurofilament phosphorylation in axotomised and 6-OH-dopamine-lesioned CNS neurons
Brain. Res.
(1990)
J. Kong et al.
Over-expression of neurofilament subunit NF-L and NF-H extends survival of a mouse model for amylotrophic lateral sclerosis
Neurosci. Lett.
(2000)
Y. Matsuoka et al.
Lack of nigral pathology in transgenic mice expressing human alpha-synuclein driven by the tyrosine hydroxylase promoter
Neurobiol. Dis.
(2001)
J. Morrison et al.
A monoclonal antibody to non-phosphorylated neurofilament protein marks the vulnerable cortical neurons in Alzheimer's disease
Brain. Res.
(1987)
C.E. Shepherd et al.
Neurofilament-immunoreactive neurons are not selectively vulnerable in Alzheimer's disease
Neurobiol. Dis.
(2001)
W. Tetzlaff et al.
Reductions in motoneuronal neurofilament synthesis by successive axotomies: A possible explanation for the conditioned lesioning effect on axon regeneration
Exp. Neurol.
(1996)

H. Braak et al.

Neuropathological staging of Alzheimer-related changes

Acta Neuropathol.

(1991)

M. Broe et al.

Relationship between DNA fragmentation, morphological changes and neuronal loss in Alzheimer's disease and dementia with Lewy bodies

Acta Neuropathol.

(2001)

L. Cork et al.

Phosphorylated neurofilament antigens in neurofibrillary tangles in Alzheimer's disease

J. Neuropathol. Exp. Neurol.

(1986)

S. Couillard-Deprez et al.

Protective effect of neurofilament heavy gene over-expression in motor neuron disease induced by mutant superoxide dismutase

Proc. Natl. Acad. Sci. USA

(1998)

S. Coulliard-Despres et al.

Extra axonal neurofilaments do not exacerbate disease caused by mutant Cu,Zn superoxide dismutase

Neurobiol. Dis.

(2000)

T. Duong et al.

Immunoreactivity patterns in neurofibrillary tangles of the inferior temporal cortex in Alzheimer's disease

Mol. Chem. Neuropathol.

(1994)

J. Galvin et al.

Axon pathology in Parkinson's disease and Lewy body dementia hippocampus contains alpha, beta and gamma synuclein

Proc. Natl. Acad. Sci. USA

(1999)

T. Gomez-Isla et al.

Clinicopathological correlates in temporal cortex in dementia with Lewy bodies

Neurology

(1999)

E. Gomez-Tortosa et al.

Cortical neurons expressing calcium binding proteins are spared in dementia with Lewy bodies

Acta. Neuropathol.

(2001)

H.J.G. Gundersen et al.

Some new, simple and efficient stereological methods and their use in pathological research and diagnosis

APMIS

(1988)

Halasz, P, &, Martin, P. 1985, Magellan program for quantitative analysis of histological sections. University of New...

J. Harasty et al.

Specific temporoparietal gyral atrophy reflects the pattern of language dissolution in Alzheimer's disease

Brain

(1999)

Cited by (36)

Biofluid Markers of Equine Neurological Disorders Reviewed From Human Perspectives
2020, Journal of Equine Veterinary Science
Citation Excerpt :
In fact, the NFs subunits are found in appreciable quantities in CSF, serum, and plasma of human with ALS, Alzheimer disease (AD), Huntington’s disease (HD), Guillain-Barré-syndrome (GBS), traumatic brain or spinal cord injury, diabetic peripheral neuropathy, and immune-mediated optic neuropathies [20,22,37–40]. It has been suggested that NFs are involved in the pathology of several human neurodegenerative diseases, including ALS, AD, and amyotrophic Lewy body formation in PD, Charcot-Marie-Tooth disease infantile spinal muscular atrophy, hereditary sensory-motor neuropathy, and giant axonal neuropathy [41–43]. Presently, the significance of NF-L in domestic animals is unknown, although it was recently shown that pNF-H is a potential biomarker for neurological diseases such as CVM, EPM, acute EGS, brain injury in foal with neonatal hypoxemic–ischemic encephalopathy, and spinal injury in dogs with intervertebral disc herniation [3,6–8,44].
Neurological disorders (NDs) are often fatal to horses. Thus, symptoms of equine NDs commonly indicate euthanasia. Current diagnostic approaches for equine NDs is based on clinical signs, differential diagnoses, analysis of cerebrospinal fluid (CSF), assessment of histopathological lesions, and imaging. However, advances in biofluid biomarkers in the diagnosis of human neurological diseases can potentially be applied to equine NDs. In this review, we described the established human blood and CSF neurobiomarkers that could potentially be used to diagnose equine NDs.
Neuroprotection with Estradiol in Experimental Perinatal Asphyxia: A New Approach. A New Approach.
2015, Estrogen Effects on Traumatic Brain Injury: Mechanisms of Neuroprotection and Repair
Perinatal asphyxia is an obstetric complication that can induce serious complications in the central nervous system. Between 15% and 20% of newborns die immediately after birth and 25% survive with varied neurological deficits such as cerebral palsy, mental retardation and developmental delay. Although different treatments have been used, thus far only hypothermia is recommended as a routine treatment in clinical practice. In this chapter we will discuss the use of estradiol and its impact on the long-term deficits induced by perinatal asphyxia.
Oxidative modification of neurofilament-L and neuronal cell death induced by the catechol neurotoxin, tetrahydropapaveroline
2013, Toxicology Letters
Citation Excerpt :
The results suggest that the modification of NF-L may be related to THP-mediated cell death. NF proteins specifically expressed in neurons and axons, have been implicated in a range of neurodegenerative disorders including amyotrophic lateral sclerosis (Collard et al., 1995), Alzheimer's disease (Shepherd et al., 2002) and Parkinson's disease (Rahner et al., 2002). The feature common to all of these disorders is the slow accumulation of NF aggregates in neuronal cells, which is accompanied by cell death.
Tetrahydropapaveroline (THP), which is an endogenous neurotoxin, has been suspected to be associated with dopaminergic neurotoxicity of l-DOPA. In this study, we examined oxidative modification of neurofilament-L (NF-L) and neuronal cell death induced by THP. When disassembled NF-L was incubated with THP, protein aggregation was increased in a time- and THP dose-dependent manner. The formation of carbonyl compounds and dityrosine were observed in the THP-mediated NF-L aggregates. Radical scavengers reduced THP-mediated NF-L modification. These results suggest that the modification of NF-L by THP may be due to oxidative damage resulting from the generation of reactive oxygen species (ROS). When THP exposed NF-L was subjected to amino acid analysis, glutamate, proline and lysine residues were found to be particularly sensitive. We also investigated the effects of copper ions on THP-mediated NF-L modification. At a low concentration of THP, copper ions enhanced the modification of NF-L. Treatment of C6 astrocyte cells with THP led to a concentration-dependent reduction in cell viability. When these cells were treated with 100 μM THP, the levels of ROS increased 3.5-fold compared with control cells. Furthermore, treatment of cells with THP increased NF-L aggregate formation, suggesting the involvement of NF-L modification in THP-induced cell damage.
Estradiol therapy in adulthood reverses glial and neuronal alterations caused by perinatal asphyxia
2010, Experimental Neurology
The capacity of the ovarian hormone 17β-estradiol to prevent neurodegeneration has been characterized in several animal models of brain and spinal cord pathology. However, the potential reparative activity of the hormone under chronic neurodegenerative conditions has received less attention. In this study we have assessed the effect of estradiol therapy in adulthood on chronic glial and neuronal alterations caused by perinatal asphyxia (PA) in rats. Four-month-old male Sprague–Dawley rats submitted to PA just after delivery, and their control littermates, were injected for 3 consecutive days with 17β estradiol or vehicle. Animals subjected to PA and treated with vehicle showed an increased astrogliosis, focal swelling and fragmented appearance of MAP-2 immunoreactive dendrites, decreased MAP-2 immunoreactivity and decreased phosphorylation of high and medium molecular weight neurofilaments in the hippocampus, compared to control animals. Estradiol therapy reversed these alterations. These findings indicate that estradiol is able to reduce, in adult animals, chronic reactive astrogliosis and neuronal alterations caused by an early developmental neurodegenerative event, suggesting that the hormone might induce reparative actions in the Central Nervous System (CNS).
Neurofilament protein aggregation in a cell line model system
2008, Biochemical and Biophysical Research Communications
Protein aggregates are associated with many diseases and even aggregates of proteins that have no role in disease are inherently toxic to both neuronal and non-neuronal cells. We have developed a model system to explore the mechanism of protein aggregation using a mouse muscle cell line expressing chimeric neurofilament (NF) proteins, a constituent of the protein aggregates in ALS, Lewy body dementia, and Charcot-Marie-Tooth disease. Formation of protein aggregates in these cells leads to reduced cell viability and activated caspases. Aggregates contained both chimeric NF proteins and ubiquitin by immunolocalization and were predominately cytosolic when proteins were expressed at low levels or for shorter periods of time but were present in the nucleus when expression levels increased. This system represents a flexible, new tool to decipher the molecular mechanism of protein aggregation and the contributions of aggregation to cell toxicity.
In vitro assay of neurofilament light chain self-assembly using truncated mutants
2007, Journal of Neuroscience Methods
Neurofilaments (NFs) are heteropolymers composed of light (NF-L), middle (NF-M), and heavy (NF-H) subunits, present in most neurons. NF-L polymerizes on its own to provide a scaffold on which regular NFs form via the cross-bridging of NF-M or NF-H. To clarify the mechanism of regulation of NF-L self-assembly, we developed an assay using truncated mutant NF-L fused to glutathione-S transferase (GST). Western immunoblotting data show that the GST-fused head–rod domains of NF-L are necessary and sufficient for detecting assembled NF-L. The levels of self-assembled NF-L subunits detected using GST fusion proteins were consistent with those detected by electron microscopy and turbidity assay. Our results collectively imply that GST-fused head–rod domains of NF-L are critical tools for analyzing NF-L self-assembly in vitro.

View all citing articles on Scopus

View full text

Regular ArticleNeurofilament-Immunoreactive Neurons in Alzheimer's Disease and Dementia with Lewy Bodies

Abstract

Am. J. Pathol.

Neuroscience

Neurobiol. Aging.

Neuron

Brain. Res.

Neurosci. Lett.

Neurobiol. Dis.

Brain. Res.

Neurobiol. Dis.

Exp. Neurol.

Neuropathological staging of Alzheimer-related changes

Acta Neuropathol.

Relationship between DNA fragmentation, morphological changes and neuronal loss in Alzheimer's disease and dementia with Lewy bodies

Acta Neuropathol.

Phosphorylated neurofilament antigens in neurofibrillary tangles in Alzheimer's disease

J. Neuropathol. Exp. Neurol.

Protective effect of neurofilament heavy gene over-expression in motor neuron disease induced by mutant superoxide dismutase

Proc. Natl. Acad. Sci. USA

Extra axonal neurofilaments do not exacerbate disease caused by mutant Cu,Zn superoxide dismutase

Neurobiol. Dis.

Immunoreactivity patterns in neurofibrillary tangles of the inferior temporal cortex in Alzheimer's disease

Mol. Chem. Neuropathol.

Axon pathology in Parkinson's disease and Lewy body dementia hippocampus contains alpha, beta and gamma synuclein

Proc. Natl. Acad. Sci. USA

Clinicopathological correlates in temporal cortex in dementia with Lewy bodies

Neurology

Cortical neurons expressing calcium binding proteins are spared in dementia with Lewy bodies

Acta. Neuropathol.

Some new, simple and efficient stereological methods and their use in pathological research and diagnosis

APMIS

Specific temporoparietal gyral atrophy reflects the pattern of language dissolution in Alzheimer's disease

Brain

Regular Article
Neurofilament-Immunoreactive Neurons in Alzheimer's Disease and Dementia with Lewy Bodies