Progressive transformation of the cytoskeleton associated with normal aging and Alzheimer's disease

doi:10.1016/0006-8993(92)91134-Z

Brain Research

Volume 594, Issue 2, 30 October 1992, Pages 273-278

https://doi.org/10.1016/0006-8993(92)91134-Z Get rights and content

Abstract

Transitional and end-stage forms of neurofibrillary tangles associated with normal aging and Alzheimer's disease were identified using thioflavine staining combined with tau and neurofilament protein immunofluorescence. Normal aging was marked by transitional pathology in layer II of the entorhinal cortex but no neurofibrillary tangles in prefrontal cortex, in Alheimer's disease cases, layer II entorhinal neurons had progressed to end-stage neurofibrillary tangles and the prefrontal cortex contained a hign representation of transitional forms of the neurofibrillary tangle.

References (39)

M.J. Ball et al.
A new definition of Alzheimer's disease: a hippocampal dementia
Lancet
(1985)
H. Braak et al.
Ratio of pyramidal cells versus non-pyramidal cells in the human frontal isocortex and changes in ratio with ageing and Alzheimer's disease
S. Cammarata et al.
Formic acid treatment exposes hidden neurofilament and tau epitopes in abnormal cytoskeletal filaments from patients with progressive supranuclear palsy and Alzheimer's disease
Neurosci. Lett.
(1990)
A. Delacourte et al.
Alzheimer's disease: tau proteins, the promoting factors of microtubule assembly, are major components of paired helical filaments
J. Neurol. Sci.
(1986)
S. Flament et al.
Characterization of two pathological tau variants in Alzheimer brain cortices
J. Neurol. Sci.
(1989)
I. Grundke-Iqbal et al.
Microtubule-associated polypeptides are altered in Alzheimer paired helical filaments
Mol. Brain Res.
(1988)
P.R. Hof et al.
Neocortical neuronal subpopulations labeled by a monoclonal antibody to calbindin exhibit differential vulnerability in Alzheimer's disease
Exp. Neurol.
(1991)
H. Ksiezak-Reding et al.
Structural stability of paired helical filaments requires microtubule-binding domains of tau: a model for self-association
Neuron
(1991)
J.H. Morrison et al.
A monoclonal antibody to non-phosphorylated neurofilament protein marks the vulnerable cortical neurons in Alzheimer's disease
Brain Res.
(1987)
J.L. Price et al.
The distribution of tangles, plaques and related immunohistochemical markers in healthy aging and Alzheimer's disease
Neurobiol. Aging
(1991)

J.C. Vickers et al.

Neurofilament protein-triplet immunoreactivity in distinct subpopulations of peptide-containing neurons in the guinea-pig coeliac ganglion

Neuroscience

(1990)

J.C. Vickers et al.

Complementary immunohistochemical distribution of the neurofilament triplet and novel intermediate filament proteins in the autonomic and sensory nervous system of the guinea-pig

J. Chem. Neuroanat.

(1991)

J.C. Vickers et al.

The neurofilament triplet is present in distinct subpopulations of neurons in the central nervous system of the guinea-pig

Neuroscience

(1992)

G.K. Wilcock et al.

Plaques, tangles and dementia

J. Neurol. Sci.

(1982)

P.V. Arriagada et al.

Neurofibrillary tangles but not senile plaques parallel duration and severity of dementia

Neurology

(1992)

W. Bondareff et al.

Molecular analysis of neurofibrillary degeneration in Alzheimer's disease

Am. J. Pathol.

(1990)

H. Braak et al.

Neuropathological stageing of Alzheimer-related changes

Acta Neuropathol.

(1991)

A. Défossez et al.

Alzheimer's disease: a new evidence for common epitopes between microtubule associated protein tau and paired helical filaments (PHF)

Virchows Arch.

(1988)

M.M. Esiri et al.

A quantitative study of the neurofibrillary tangles and the choline acetyltransferase activity in the cerebral cortex and the amygdala in Alzheimer's disease

J. Neurol. Neurosurg. Psychiatry

(1990)

Cited by (92)

SMI-32 labeling in Cajal-Retzius cells of feline primary visual cortex
2021, Neuroscience Letters
Citation Excerpt :
The Cajal-Retzius cells are extremely important for corticogenesis [3]. Whereas an expression of the HNF is a useful tool for the study for the pathogenesis of some neurological diseases like Alzheimer’s disease [24–27], Parkinson disease [28], lateral amyotrophic sclerosis [29], the HNF could be an interesting target for pathomorphological investigations related to study the corticogenesis deviations. Althoug, cat as a model are not so much common these days like it previously was, they still appear since that animal is much more suitable than rodents, for studying many phenomena for example, visual system development [30,15], locomotion and posture [31,32].
Cajal-Retzius cells are one of the transient elements of the developing cerebral cortex. These cells express some characteristic molecules. One of them, heavy-chain neurofilaments, participating in the construction of the mature cerebral networks, are believed to be a specific feature of the human’s Cajal-Retzius cells. Using histochemical stain for SMI-32 antibody to the non-phosphorylated heavy-chain neurofilaments, large neurons having horizontally oriented soma and bipolar processes were labeled in the molecular layer of the primary visual cortex of cats aged 0–2 postnatal days. Using DiI technique, similar neurons having a well-developed system of parallel vertical branches coming from the two horizontal processes were visualized in these areas. The location and general morphology of these neurons were similar to the Cajal-Retzius cells allowing to suppose for the carnivores to share similar with primates developmental mechanisms of the corticogenesis.
Combination treatment with leptin and pioglitazone in a mouse model of Alzheimer's disease
2017, Alzheimer's and Dementia: Translational Research and Clinical Interventions
Combination therapy approaches may be necessary to address the many facets of pathologic change in the brain in Alzheimer's disease (AD). The drugs leptin and pioglitazone have previously been shown individually to have neuroprotective and anti-inflammatory actions, respectively, in animal models.
We studied the impact of combined leptin and pioglitazone treatment in 6-month-old APP/PS1 (APPswe/PSEN1dE9) transgenic AD mouse model.
We report that an acute 2-week treatment with combined leptin and pioglitazone resulted in a reduction of spatial memory deficits (Y maze) and brain β-amyloid levels (soluble β-amyloid and amyloid plaque burden) relative to vehicle-treated animals. Combination treatment was also associated with amelioration in plaque-associated neuritic pathology and synapse loss, and also a significantly reduced neocortical glial response.
Combination therapy with leptin and pioglitazone ameliorates pathologic changes in APP/PS1 mice and may represent a potential treatment approach for AD.
Alterations in neurofilaments and the transformation of the cytoskeleton in axons may provide insight into the aberrant neuronal changes of Alzheimer's disease
2016, Brain Research Bulletin
Citation Excerpt :
These ageing brain-related NFTs are predominantly intracellular and not linked to overt nerve cell death (Vickers et al., 1992a). This does likely make the cells particularly vulnerable to degeneration, as the entorhinal cortex also shows a relative abundance of ghost tangles at end-stage AD (Vickers et al., 1992a). With respect to end-stage AD, most NFTs in neocortical areas are still intracellular (Vickers et al., 1992a, 2003), further suggesting that tangle-related neurodegeneration is a slow process.
Neurofilaments are major protein constituents of the brain, but are particularly abundant in specific subpopulations of neurons and likely have a key role in the regulation of axonal calibre. Neurofilament proteins may also be involved in the transformation of the neuronal cytoskeleton leading to substantial tau pathology in axons damaged by Aβ, subsequently leading to neurofibrillary pathology in their cell bodies of origin. An understanding of neurofilamentous changes in axons and subsequent tau pathology may provide insight into how Aβ pathology may stimulate an aberrant plasticity-related response of damaged neurons, leading to the progressive and degenerative changes in the neuronal cytoskeleton that result in synapse loss and neuronal degeneration.
Neurofilament light gene deletion exacerbates amyloid, dystrophic neurite, and synaptic pathology in the APP/PS1 transgenic model of Alzheimer's disease
2015, Neurobiology of Aging
Citation Excerpt :
It lacks substantial tau pathology (Howlett et al., 2008) but demonstrates Aβ plaque–associated DNs with accumulations of NFs, α-internexin, synaptic proteins (Mitew et al., 2013b), and plaque-associated synapse loss (Mitew et al., 2013a). Notably, we were particularly interested in the effect of the diminution of NFs on DNs, as NF triplet–containing cortical neurons are selectively vulnerable to AD pathology (Hof and Morrison, 1991; Mitew et al., 2013b; Morrison et al., 1987; Vickers and Costa, 1992; Vickers et al., 1992b, 1994) and NF-containing DNs are the earliest neuronal change associated with Aβ plaque formation in the human brain (Dickson et al., 1999; Vickers et al., 1996). However, unexpectedly, our results showed that NFL deficiency in the APP/PS1 model increased neocortical neurite and synapse vulnerability to Aβ plaques and Aβ plaque pathology.
Alzheimer's disease (AD) is a progressive neurodegenerative disease associated with the loss of cognitive function. Neurofilament (NF) triplet proteins, the major structural (intermediate filament) proteins of neurons, are expressed in a subset of pyramidal cells that show a high degree of vulnerability to degeneration in AD. Alterations in the NF triplet proteins in amyloid-beta (Aβ) plaque-associated dystrophic neurites (DNs) represent the first cytoskeletal aberration to occur in the neocortex in the earliest stages of AD. We generated transgenic APP/PS1 (APPswe/PSEN1dE9) mice on the neurofilament light knockout (NFL KO) background to explore the role of NFL deletion in the context of DN formation, synaptic changes, and other neuropathologic features. Our analysis demonstrated that NFL deficiency significantly increased neocortical DN pathology, Aβ deposition, synapse vulnerability, and microgliosis in APP/PS1 mice. Thus, NFs may have a role in protecting neurites from dystrophy and in regulating cellular pathways related to the generation of Aβ plaques.
Life and Death of Neurons in The Aging Cerebral Cortex
2007, International Review of Neurobiology
Citation Excerpt :
The association cortices are known to be involved in many aspects of cognition (Goldman‐Rakic, 1988). In AD, neurofilament protein–enriched neurons in certain neocortical and hippocampal areas are dramatically affected and die during NFT formation (Hof and Morrison, 1990, 2004; Hof et al., 1990; Morrison and Hof, 1997; Morrison et al., 1987; Vickers, 1997; Vickers et al., 1992, 1994, 2000). If the monkey data are considered within the context of the distribution of neurofilament protein–enriched neurons and NFTs in humans, it is likely that the human homologues of the neurofilament protein–enriched, corticocortically projecting neurons in the macaque monkey are those that are highly vulnerable in human AD.
The transition from age‐associated memory impairment (AAMI) to the dramatic loss of cognitive abilities accompanying Alzheimer's disease (AD) requires progressive development of neocortical pathology that results in neuron death. The selective vulnerability of this neuron death is reflected in the characteristics of cortical pyramidal neurons that are prone to form neurofibrillary tangles. Loss of the neurons that form long corticocortical projections in the association neocortex emerges as the pathological outcome most directly related to the dementia observed in AD. AAMI likely involves alterations of neuronal spines and synapses without neuron death. Interestingly, the same circuits that are vulnerable to degeneration in AD are vulnerable to synaptic alterations short of neuron death. These synaptic alterations likely impact cognitive function in normal aging in a manner consistent with the more modest cognitive decline typically seen in aging. Estrogen levels affect spine density on pyramidal neurons in the prefrontal cortex; these neurons may provide many of the same circuits implicated in AAMI. This association demonstrates an important interface between reproductive and neural senescence and suggests that the synaptic alterations prevalent in normal aging may be responsive to therapy.
α-Internexin immunoreactivity reflects variable neuronal vulnerability in Alzheimer's disease and supports the role of the β-amyloid plaques in inducing neuronal injury
2005, Neurobiology of Disease
This study investigated the role of α-internexin in the neuronal alterations associated with β-amyloid plaque formation in Alzheimer's disease (AD). Cortical neurons could be defined by their variable content of neurofilament (NF) triplet and α-internexin proteins, with a distinct population of supragranular pyramidal cells containing α-internexin alone. Both NF triplet and α-internexin were localized to reactive axonal structures in physically damaged neurons in experimental trauma models. Similarly, NF triplet and α-internexin immunoreactive neurites were localized to plaques densely packed with β-amyloid fibrils in preclinical AD cases, indicating that certain plaques may cause structural injury or impediment of local axonal transport. However, α-internexin, and not NF triplet, ring-like reactive neurites were present in end-stage AD cases, indicating the relatively late involvement of neurons that selectively contain α-internexin. These results implicate the expression of specific intermediate filament proteins in a distinct hierarchy of differential neuronal vulnerability to AD.

View all citing articles on Scopus

^☆: This work was funded by AG05138 and AG06647 from the National Institute for Aging and AHAF.

^∗∗: We would like to thank our colleagues at the Fishberg Research Center for neurobiology as well as Dr. John Trojanowski and Dr. Neil Kowall for their valued comments on the manuscript. We also thank William Janssen for technical support and Bob Woolley for photographic assistance. In addition, we would like to acknowledge the Institute of Biogerontology Research Tissue Donation Program (Sun City, Arizona) for the provision of many of the cases in the present study.

View full text

Short communicationProgressive transformation of the cytoskeleton associated with normal aging and Alzheimer's disease☆

Abstract

Lancet

Neurosci. Lett.

J. Neurol. Sci.

J. Neurol. Sci.

Mol. Brain Res.

Exp. Neurol.

Neuron

Brain Res.

Neurobiol. Aging

Neuroscience

J. Chem. Neuroanat.

Neuroscience

J. Neurol. Sci.

Neurofibrillary tangles but not senile plaques parallel duration and severity of dementia

Neurology

Molecular analysis of neurofibrillary degeneration in Alzheimer's disease

Am. J. Pathol.

Neuropathological stageing of Alzheimer-related changes

Acta Neuropathol.

Alzheimer's disease: a new evidence for common epitopes between microtubule associated protein tau and paired helical filaments (PHF)

Virchows Arch.

A quantitative study of the neurofibrillary tangles and the choline acetyltransferase activity in the cerebral cortex and the amygdala in Alzheimer's disease

J. Neurol. Neurosurg. Psychiatry

Short communication
Progressive transformation of the cytoskeleton associated with normal aging and Alzheimer's disease☆