Biomedical subjects

Thomas Arendt

Publications and source records attributed to Thomas Arendt.

At least 37 records · Page 2Linked to original sources

PubMed2005

The carbonyl scavengers aminoguanidine and tenilsetam protect against the neurotoxic effects of methylglyoxal.

Advanced glycation end products (AGEs) have been identified in age-related intracellular protein deposits of Alzheimer's disease (amyloid plaques and neurofibrillary tangles) and Parkinson disease (Lewy bodies), suggesting that these protein deposits have been exposed to AGE precursors such as the reactive dicarbonyl compound methylglyoxal. In ageing tissue and under diabetic pseudohypoxia, intracellular methylglyoxal levels rise through an impairment of triosephosphate utilization. Furthermore, methylglyoxal detoxification is impaired when reduced glutathione levels are low, conditions, which have all been described in Alzheimer's disease. However, there is less known about the toxicity of methylglyoxal, particularly about therapeutic strategies to scavenge such dicarbonyl compounds and attenuate their toxicity. In our study, extracellularly applied methylglyoxal was shown to be toxic to human neuroblastoma cells in a dose-dependent manner above concentrations of 150 microM with a LD50 of approximately 1.25 mM. Pre-incubation of methylglyoxal with a variety of carbonyl scavengers such as aminoguanidine or tenilsetam and the thiol antioxidant lipoic acid significantly reduced its toxicity. In summary, carbonyl scavengers might offer a promising therapeutic strategy to reduce the neurotoxicity of reactive carbonyl compounds, providing a potential benefit for patients with age-related neurodegenerative diseases.

Cell Line, Tumor↗

PubMed2005

Expression of cell cycle-related proteins in developing and adult mouse hippocampus.

Developmental structuring of brain is the result of a strictly coordinated process that involves controlled cell division, neuronal migration and terminal differentiation. Neurogenesis occurs generally during embryonic and early postnatal stages and will be finished in the mature brain. Once differentiated, neurons are incapable of further division but retain the capability of structural and functional plasticity. However, there are distinct regions in the adult brain of mammals that generate neurons continuously throughout life. Among them, the hippocampus, which is known as a region with a high degree of neuroplasticity, is of particular interest in the context of adult neurogenesis. In general, progression through cell cycle phases is regulated by the sequential expression and activation of regulatory proteins like cyclin dependent kinases (cdk), cyclins, or cdk inhibitors (cdki). In postmitotic and terminally differentiated neurons, cell cycle activity is arrested by enrichment of cdkis. The timing of cell cycle exit and neuronal differentiation is likely to be regulated in part by cell cycle regulatory proteins. However, the expression of cell cycle markers in the postnatal or adult brain is still a matter of controversial debate. In the present study, we examined the expression of cdks, cyclins and cdkis within the mouse hippocampus at different developmental stages (embryonic days 17, 19; postnatal day 11 and adult) using immunohistochemical methods. During the prenatal development, cell cycle proteins were localized predominantly in nuclei of all presumptive neuronal populations but expression was not restricted to proliferative cells. With developmental progression, the subcellular localization of most markers was increasingly shifted from nuclear to the cytoplasmic compartment. However, even in the adult, cell cycle-related proteins were found in terminally differentiated pyramidal and granule neurons. Here, they were mainly localized in the perikaryal cytoplasm but only sporadically in neuronal nuclei. Occasionally, immunoreactivity was also found in dendrites and mossy fibers. The present results suggest that cell cycle arrest and terminal differentiation is not necessarily incompatible with the expression of cell cycle-related markers. Thus, they may have supplementary functions in differentiated neurons that might be associated with neuronal plasticity.

Aging↗

PubMed2005

Reelin-immunoreactivity in the hippocampal formation of 9-month-old wildtype mouse: effects of APP/PS1 genotype and ovariectomy.

Reelin, an extracellular matrix protein has an important role in the migration, correct positioning and maturation of neurons during development. Though it is generally down-regulated in the postnatal period, expression of this large glycoprotein continues in the adult brain in some cell populations. In the present study, we examined the distribution of reelin-immunoreactivity (-ir) in the hippocampal formation of 9-month-old wildtype mice (WT). Then, reelin-ir in normal mice was compared to that of transgenic mice (APP/PS1) carrying mutated human APP and PS1 genes, which are linked to the familial form of Alzheimer's disease (AD). The APP/PS1 mice were additionally burdened with a second risk factor for AD, namely depletion of circulating gonadal hormones by ovariectomy (APP/PS1 + OVX). The analyses revealed that in adult WT reelin-ir is expressed by Cajal-Retzius cells and a subgroup of interneurons throughout the hippocampal formation. In addition, layer II projection neurons in the lateral entorhinal subfields are reelin-ir. Interestingly, ovariectomy decreases the number of reelin-ir cells in the hilus in WT mice, whereas AD-related genotype alone induces only a non-significant reduction. Unexpectedly, additional stress, e.g., depletion of gonadal hormones, does not aggravate the slight reduction in the reelin cell number in the APP/PS1 mice. We propose that the changes in normal reelin-ir are linked to disturbances in repair mechanisms in which APP/PS1 and gonadal hormones are involved and which are perturbed in neurodegenerative conditions, namely AD.

Alzheimer Disease↗

PubMed2005

Immunochemical crossreactivity of antibodies specific for "advanced glycation endproducts" with "advanced lipoxidation endproducts".

Antibodies against advanced glycation endproducts (AGEs) are used for their immunohistological localization in tissues, for example in Alzheimer's disease (AD) or diabetes. Many monoclonal and polyclonal antibodies have been used, and their specificity is unknown in most cases. Increased radical production, leading to the formation of lipid-derived reactive carbonyl species, such as malondialdehyde (MDA), acrolein, and glyoxal, is a characteristic aspect of age-related diseases like Alzheimer's disease or diabetic polyneuropathy. These reactive carbonyl species are able to modify proteins, resulting in AGE related structures, termed "advanced lipoxidation products" (ALEs). In this study, the monoclonal carboxymethyllysine-specific antibody 4G9 and the polyclonal AGE-antibody K2189 were tested for their immunoreactivity towards these carbonyl-derived protein modifications. To investigate which carbonyl-modified amino acid side chains are specifically recognized by these antibodies, peptide membranes were incubated with glyoxal, MDA and acrolein. As model proteins, microtubuli associated protein tau (MAP-tau), beta-amyloid, human serum albumin and chicken egg albumin were incubated likewise. It was found that both antibodies detected reaction products of these carbonyl compounds on lysine- and arginine residues and for the protein modification, it was found that some epitopes might not be detected. In conclusion, AGE-antibodies might not only detect sugar-derived AGEs but also structures derived from lipid peroxidation products (serving as markers of oxidative stress).

Alzheimer Disease↗

PubMed2005

Alzheimer's disease as a disorder of dynamic brain self-organization.

Mental function is based on the dynamic organization of neuronal networks. In particular, phylogenetically young brain areas (e.g., cortical associative circuits), involved in the realization of "higher brain functions" such as learning, memory, perception, self-awareness, and consciousness, are continuously re-adjusted even after development is completed. By this life-long self-optimization process, epigenetic information remodels the cognitive, behavioral and emotional reactivity of an individual to meet the environmental demands. To organize brain structures of increasing complexity during evolution, the process of selective dynamic stabilization and destabilization of synaptic connections becomes more and more important. The mechanisms of structural stabilization and labilization underlying a lifelong synaptic remodeling according to experience, are accompanied, however, by an increasing inherent potential of failure and may, thus, not only allow for the evolutionary acquisition of "higher brain function" but at the same time may provide the basis for selective neuronal vulnerability. The mechanisms of synaptic plasticity, i.e., of modifiable interneuronal connectivity, are largely based on external morphoregulatory cues and internal signaling pathways that nonneuronal cells have phylogenetically acquired to sense their relationship to the local neighborhood and to control proliferation and differentiation in the process of tissue repair and regeneration after development is completed. Differentiated neurons that have withdrawn from the cell cycle use these molecular machinery alternatively to control synaptic plasticity. The existence of these alternative effector pathways within a neuron puts it on the risk to erroneously convert signals derived from plastic synaptic changes into positional cues that will activate the cell cycle. This cell cycle activation potentially links synaptic plasticity to cell death. Preventing cell cycle activation by locking neurons in a differentiated but still highly plastic phenotype will, thus, be crucial to prevent neurodegeneration.

Alzheimer Disease↗

PubMed2005

Inducible neuronal expression of transgenic TGF-beta1 in vivo: dissection of short-term and long-term effects.

Various chronic neurological diseases are associated with increased expression of transforming growth factor-beta1 (TGF-beta1) in the brain. TGF-beta1 has both neuroprotective and neurodegenerative functions, depending on conditions such as duration and the local and temporal pattern of its expression. Previous transgenic approaches did not enable control for these dynamic aspects. To overcome these limitations, we established a transgenic mouse model with inducible neuron-specific expression of TGF-beta1 based on the tetracycline-regulated gene expression system. TGF-beta1 expression was restricted to the brain where it was particularly pronounced in the neocortex, hippocampus and striatum. Transgene expression was highly sensitive to the presence of doxycycline and completely silenced within 6 days after doxycycline application. After long-term expression, perivascular thioflavin-positive depositions, formed by amyloid fibrils, developed. These depositions persisted even after prolonged silencing of the transgene, indicating an irreversible process. Similarly, strong perivascular apolipoprotein E (ApoE) depositions were found after TGF-beta1 expression and these remained despite TGF-beta1 removal. These in vivo observations suggests that the continuous presence of TGF-beta1 as initial trigger is not necessary for the persistence and development of chronic lesions. Neuroprotective effects were observed after short-term expression of TGF-beta1. Death of striatal neurons induced by 3-nitropropionic acid was markedly reduced after induced TGF-beta1 expression.

Animals↗

PubMed2005

Methylglyoxal, glyoxal, and their detoxification in Alzheimer's disease.

The accumulation of advanced glycation end products (AGEs) in brains with Alzheimer's disease (AD) has been implicated in the formation of insoluble deposits such as amyloid plaques and neurofibrillary tangles. AGEs are also known to activate glia, resulting in inflammation and neuronal dysfunction. As reactive intermediates of AGE formation, neurotoxic reactive dicarbonyl compounds such as glyoxal and methylglyoxal have been identified. One of the most effective detoxification systems for methylglyoxal and glyoxal is the glutathione-dependent glyoxalase system, consisting of glyoxalase I and glyoxalase II. In this study, we have determined the methylglyoxal and glyoxal levels in the cerebrospinal fluid of AD patients compared to healthy controls. Methylglyoxal levels in AD patients were twofold higher than in controls, but this difference was not significant due to the large intergroup variations and the small sample size. However, the concentrations of both compounds were five to seven times higher in CSF than in plasma. We also investigated the glyoxalase I level in AD and healthy control brains. The number of glyoxalase I- positive neurons were increased in AD brains compared to controls. Our findings suggest that glyoxalase I is upregulated in AD in a compensatory manner to maintain physiological methylglyoxal and glyoxal levels.

Aged↗

PubMed2005

The expression of cell cycle proteins in neurons and its relevance for Alzheimer's disease.

Alzheimer's disease is a chronic neurodegenerative disorder characterised by typical pathological hallmarks such as amyloid deposition, neurofibrillary tangles and disturbances in the expression of various cell cycle proteins. A current pathogenetic hypothesis suggests that neurons, forced by external and internal factors, leave the differentiated G(0) phase and re-enter the cell cycle. This process results in neuronal de-differentiation and apoptosis and might contribute to an increased phosphorylation of the tau protein. There are a number of reports, however, describing the expression of cell cycle proteins in rodent or human brain under normal non-disease conditions. This might indicate that cell cycle expression of proteins in neurons is of physiological rather than pathophysiological relevance. Therefore, it needs to be carefully analysed whether the expression of cell cycle regulators such as cyclin-dependent kinases, cyclins or cyclin-dependent kinase inhibitors in neurons is a pathological hallmark that allows to discriminate between normal and disease condition. Here we attempt to summarise recent evidence for a dysfunction of cell cycle regulators in Alzheimer's disease, considering the potential functions of these molecules beyond cell cycle regulation.

Alzheimer Disease↗

PubMed2004

Activation of Ras in neurons modifies synaptic vesicle docking and release.

We have recently demonstrated that constitutive activation of Ha-Ras in differentiated neurons induces structural remodeling of both axons and dendrites in a transgenic mouse model (referred as synRas mice). Here we show that this activation of neuronal Ras enhances docking of synaptic vesicles to active zones, thereby leading to an increase in the size of the readily releasable pool of vesicles, while the size of the total pool of synaptic vesicles remained unchanged. The morphological phenotype was associated with corresponding increases in the probability of glutamate release as revealed by changes in short-term synaptic plasticity. We, therefore, conclude that neuronal Ras activity contributes to the regulation of synaptic plasticity in adult mammalian brain at the presynaptic level.

Animals↗

PubMed2004

Tau gene (MAPT) sequence variation among primates.

Filamentous tau deposits are a defining feature of a number of human neurodegenerative diseases. Apes and monkeys have been reported to be differentially susceptible to developing tau pathology. Despite this, only little is known about the organisation and sequence of Tau from nonhuman primates. Here we have sequenced Tau exons 1-13, including flanking intronic regions, and the region in intron 9 that contains Saitohin in chimpanzees, gorillas, and gibbons. Partial sequences were obtained for cynomolgus macaque and green monkey. Chimpanzee brain tau was 100% identical to human tau. Identities were 99.5% for gorilla tau and 99.0% for gibbon tau. Chimpanzee DNA was polymorphic for a repeat in intron 9, which was present in human and gorilla tau, and for the nucleotide at position +29 of the intron that follows exon 10. As was the case of the other nonhuman primates examined, chimpanzee DNA was homozygous for nucleotides used to define the H2 haplotype in human Tau. These differences between human and chimpanzee Tau may contribute to the apparent resistance of chimpanzee brain to developing tau pathology. Sequencing of Saitohin revealed an intact open reading frame in chimpanzee and gorilla, but not in gibbon or macaque.

Alternative Splicing↗

PubMed2004

Constitutive expression of p21H-ras(Val12) in pyramidal neurons results in reorganization of mouse neocortical afferents.

The effect of constitutive expression of p21H-ras(Val12) in pyramidal neurons upon the establishment of afferent input has been investigated in the primary somatosensory cortex of transgenic mice. In these animals, relevant transgene expression is confined to cortical pyramidal neurons and starts postnatally at a period when neuronal morphogenesis has been largely completed. We have shown recently that overexpression of p21H-ras(Val12) in these cells results in considerable enlargement of their size and consequently in expansion of the cortex. In the present study we demonstrate that the density of terminals representing intra- or interhemispheric afferents within cortical layers II/III, however, is only slightly decreased. The density of thalamocortical boutons within layer IV is even higher and the number of afferent contacts to transgenic pyramidal neurons is significantly increased compared to the wild-type. The number of catecholaminergic and cholinergic terminals is augmented proportionally to cortical size or even overproportionally, respectively. Along intercortical and striatal fibers arising from p21H-ras(Val12)-expressing pyramidal neurons, frequency of varicosities is significantly increased, but remains unchanged on cortical cholinergic and catecholaminergic axons originating from "nontransgenic" neurons. Additionally, a higher number of multiple synaptic bodies are found in transgenic mice, suggesting subtle effects on synaptic plasticity. It is concluded that the enlargement of pyramidal neurons due to transgenic expression of p21H-ras(Val12) is paralleled by significant changes in the quantity and pattern of afferent connections. Moreover, expression of p21H-ras(Val12) in pyramidal cells induces an enhanced establishment of efferent boutons.

Afferent Pathways↗

PubMed2004

Constitutive Ras activity induces hippocampal hypertrophy and remodeling of pyramidal neurons in synRas mice.

The small G protein Ras, which is involved critically in neurotrophic signal transduction, has been implicated in neuronal plasticity of both the developing and the adult nervous systems. In the present study, the cumulative effects of constitutive Ras activity from early in postnatal development into the adult upon the morphology of hippocampal pyramidal neurons were investigated in synRas mice overexpressing Val12-Ha-Ras postmitotically under the control of the rat synapsin I promoter. In synRas mice, stereologic investigations revealed hypertrophy of the hippocampus associated with an increase in perikaryal size of pyramidal neurons within the CA2/CA3 region and the gyrus dentatus. Morphometric analyses of Lucifer Yellow-filled CA1 pyramidal neurons, in addition, demonstrated considerable expansion of dendritic arbors. The increase in basal dendritic size was caused primarily by alterations of intermediate and distal segments and was associated with an enlarged dendritic surface. Apical dendrites showed similar but more moderate changes, which were attributed mainly to elongation of terminal segments. Sholl analyses illustrated higher complexity of both basal and apical trees. Despite significant morphologic alterations, dendritic arbors preserve their major design principles. The synaptic density within the stratum radiatum of CA1 remained unchanged; however, increases in the total hippocampal volume and in apical dendritic size imply an increment in the absolute number of synaptic contacts. The data presented here suggest a critical involvement of Ras dependent signaling in morphoregulatory processes during the maturation and in the maintenance of hippocampal pyramidal neurons.

Animals↗

PubMed2004

Age- and stage-dependent accumulation of advanced glycation end products in intracellular deposits in normal and Alzheimer's disease brains.

In this immunohistochemical study, the age- and stage-dependent accumulation of advanced glycation end-products (AGEs) in Alzheimer's disease (AD) and their relation to the formation of neurofibrillary tangles and neuronal cell death was investigated. For this purpose, the distribution of AGEs in neurons and glia was analyzed in the auditory association area of superior temporal gyrus (Brodmann area 22) of young and old non-demented controls and compared with early- and late-stage AD. A possible co-localization of AGEs with typical hallmarks of AD, such as hyperphosphorylated tau (as a marker for disturbed kinase/phosphatase activity), nNOS (as a marker for nitroxidative stress) and caspase-3 (as a marker of apoptotic cell death), was also investigated. Our results show that the percentage of AGE-positive neurons (and astroglia) increase both with age and, in AD patients, with the progression of the disease (Braak stages). Interestingly, nearly all if those neurons which show diffuse cytosolic AGE immunoreactivity also contain hyperphosphoryated tau, suggesting a link between AGE accumulation and the formation of early neurofibrillary tangles. Many, but not all, neurons show a co-localization of AGEs with other markers of neurodegeneration, such as nNOS and caspase-3.

Adult↗

PubMed2004

Adaptive morphological changes of neocortical interneurons in response to enlarged and more complex pyramidal cells in p21H-Ras(Val12) transgenic mice.

Morphological features of interneuronal adaptation to an altered, more complex neuronal architecture have been investigated in p21H-Ras(Val12) transgenic mice. This transgenic strain serves as a model for studying the morphogenetic role of the G-protein p21Ras on cortical principal neurons. We have recently demonstrated that postmitotic expression of constitutively active p21H-Ras(Val12) in the neocortical pyramidal cell population results in increased size and dendritic complexity of the affected neurons, leading to an enlarged cortical volume. Interneurons do not express the transgene and are therefore excluded from direct, intrinsic p21H-Ras(Val12) effects. In the present study, immunolabelling of gamma-amino-butyric-acid (GABA), and of the calcium-binding proteins parvalbumin, calbindin and calretinin revealed that in the transgenic mice local circuit neurons are not increased in either somal size or number and their main morphological characteristics are preserved. However, the dendritic arbour of interneurons was found to be extended, at least in the vertical dimension, to follow the cortical expansion. Immunostaining for the vesicular GABA transporter revealed a denser inhibitory innervation of p21H-Ras(Val12)-expressing pyramidal cell perikarya than in those of wild-type animals, while the overall density of inhibitory axon terminals within the cortex was decreased in the transgenic animals as a consequence of cortical expansion. The findings of the present study demonstrate the morphogenetic capacity of interneurons for adapting to morphological alterations of principal neurons in the cerebral cortex.

Adaptation, Physiological↗

PubMed2004

Serum lipids and hippocampal volume: the link to Alzheimer's disease?

The association between hippocampal volume (as a presumed index of Alzheimer's disease pathology) with serum total cholesterol, high-density lipoprotein cholesterol, and low-density lipoprotein cholesterol was studied in 86 elderly subjects with a range of cognitive functions. High-density lipoprotein cholesterol, but not low-density lipoprotein cholesterol or total cholesterol, was associated with hippocampal volume and dementia. This is compatible with protective effects of high-density lipoprotein cholesterol on hippocampal atrophy and Alzheimer's disease.

Aged↗

PubMed2004

Perineuronal nets potentially protect against oxidative stress.

A specialized form of extracellular matrix (ECM) termed perineuronal nets (PNs) consisting of large aggregating chondroitin sulfate proteoglycans (CSPGs), with hyaluronan and tenascin as main components, surrounds subpopulations of neurons. The glycosaminoglycan components of perineuronal nets form highly charged structures in the direct microenvironment of neurons and thus might be involved in local ion homeostasis. The polyanionic character suggests that perineuronal nets also potentially contribute to reduce the local oxidative potential in the neuronal microenvironment by scavenging and binding redox-active iron, thus providing some neuroprotection to net-associated neurons. Here, we show that neurons ensheathed by a perineuronal net in the human cerebral cortex are less frequently affected by lipofuscin accumulation than neurons without a net both in normal-aged brain and Alzheimer's disease (AD). As lipofuscin is an intralysosomal pigment composed of cross-linked proteins and lipids generated by iron-catalyzed oxidative processes, the present results suggest a neuroprotective function of perineuronal nets against oxidative stress, potentially involved in neurodegeneration.

Aged↗

PubMed2004

Enhanced Ras activity in pyramidal neurons induces cellular hypertrophy and changes in afferent and intrinsic connectivity in synRas mice.

Neurotrophic actions are critically controlled and transmitted to cellular responses by the small G protein Ras which is therefore essential for normal functioning and plasticity of the nervous system. The present study summarises findings of recent studies on morphological changes in the neocortex of synRas mice expressing Val12-Ha-Ras in vivo under the control of the rat synapsin I promoter. In the here reported model (introduced by Heumann et al. [J. Cell Biol. 151 (2000) 1537]), transgenic Val12-Ha-Ras expression is confined to the pyramidal cell population and starts postnatally at a time, when neurons are postmitotic and their developmental maturation has been basically completed. Expression of Val12-Ha-Ras results in a significant enlargement of pyramidal neurons. Size, complexity and spine density of dendritic trees are increased, which leads, finally, to cortical expansion. However, the main morphological design principles of 'transgenic' pyramidal cells remain preserved. In addition to somato-dendritic changes, expression of Val12-Ha-Ras in pyramidal cells induces augmented axon calibres and upregulates the establishment of efferent boutons. Despite the enlargement of cortical size, the overall density of terminals representing intra- or interhemispheric, specific and non-specific afferents is unchanged or even higher in transgenic mice suggesting a significant increase in the total afferent input to the neocortex. Although interneurons do not express the transgene and are therefore excluded from direct, intrinsic Val12-Ha-Ras effects, they respond with morphological adaptations to structural changes. Thus, dendritic arbours of interneurons are extended to follow the cortical expansion and basket cells establish a denser inhibitory innervation of 'transgenic' pyramidal cells perikarya. It is concluded that expression of Val12-Ha-Ras in pyramidal neurons results in remodelling of neocortical structuring which strongly implicates a crucial involvement of Ras in cortical plasticity.

Adaptation, Physiological↗

PubMed2004

Neurodegeneration and plasticity.

Neurofibrillary degeneration, associated with the formation of paired helical filaments (PHF), is one of the critical neuropathological hallmarks of Alzheimer's disease (AD). Although the microtubule-associated protein tau in a hyperphosphorylated form has been established as primary PHF constituent, the process of tau phosphorylation and its potential link to degeneration is not very well understood, mostly because of the lack of a physiological in vivo model of PHF-like tau phosphorylation. PHF formation in AD follows a hierarchical pattern of development throughout different cortical areas, which closely matches the pattern of neuronal plasticity in the adult brain. Those brain areas are most early and most severely affected which are involved in the regulation of memory, learning, perception, self-awareness, consciousness, and higher brain functions that require a life-long re-fitting of connectivity, a process based on a particularly high degree of plasticity. Failures of synaptic plasticity are, thus, assumed to represent early events in the course of AD that eventually lead to alteration of tau phosphorylation. Recently, we have used the hibernation cycle, a physiological model of adaptation associated with an extraordinary high degree of structural neuronal plasticity, to analyze the potential link between synaptic plasticity, synaptic detachment and the regulation of tau phosphorylation. During torpor, a natural state of hypothermia, synaptic contacts between mossy fibers and hippocampal pyramidal neurons undergo dramatic regressive changes that are fully reversible very rapidly during euthermy. This rapid, reversible, and repeated regression of synaptic and dendritic components on CA3 neurons is associated with a reversible PHF-like phosphorylation of tau at a similar time course. The repeated formation and degradation of PHF-tau might, thus, represent a physiological mechanism not necessarily associated with pathological effects. These findings implicate an essential link between neuronal plasticity and PHF-like phosphorylation of tau, potentially involved in neurofibrillary degeneration.

Aging↗