Katalin Majtényi

Key factors in Alzheimer's disease: β-Amyloid precursor protein processing, metabolism and intraneuronal transport

During the last years it has become evident that the β‐amyloid (Aβ) component of senile plaques may be the key molecule in the pathology of Alzheimers disease (AD). The source and place of the neurotoxic action of Aβ, however, is still a matter of controversy. The precursor of the β‐amyloid peptide is the predominantly neuronal β‐amyloid precursor protein. We, and others, hypothesize that intraneuronal misregulation of APP leads to an accumulation of Aβ peptides in intracellular compartments. This accumulation impairs APP trafficking, which starts a cascade of pathological changes and causes the pyramidal neurons to degenerate. Enhanced Aβ secretion as a function of stressed neurons and remnants of degenerated neurons provide seeds for extracellular Aβ aggregates, which induce secondary degenerative events involving neighboring cells such as neurons, astroglia and macrophages/microglia.

TARDBP variation associated with frontotemporal dementia, supranuclear gaze palsy, and chorea†

TDP‐43 has been identified as the pathological protein in the majority of cases of frontotemporal lobar degeneration and amyotrophic lateral sclerosis (ALS). TARDBP mutations have so far been uniquely associated with familial and sporadic ALS. We describe clinicopathological and genetic findings in a carrier of the novel K263E TARDBP variation, who developed frontotemporal dementia, supranuclear palsy, and chorea, but no signs of motor neuron disease. Neuropathologic examination revealed neuronal and glial TDP‐43‐immunoreactive deposits, predominantly in subcortical nuclei and brainstem. This is the first report of a TARDBP variation associated with a neurodegenerative syndrome other than ALS.

White Matter Tauopathy with Globular Glial Inclusions: A Distinct Sporadic Frontotemporal Lobar Degeneration

Frontotemporal lobar degenerations are a group of disorders characterized by circumscribed degeneration of the frontal and temporal lobes and diverse histopathologic features. We report clinical, neuropathologic, ultrastructural, biochemical, and genetic data on 7 individuals with a 4-repeat tauopathy characterized by the presence of globular glial inclusions (GGIs) in brain white matter. Clinical manifestations were compatible with the behavioral variant of frontotemporal dementia and included motor neuron symptoms; there was prominent neuronal loss in the frontal and temporal cortex, subiculum, and amygdala. The surrounding white matter showed abundant GGIs composed of abnormal filaments present mostly in oligodendrocytes. The severity of white matter tau abnormalities correlated with a reduction in myelin and axons and with microglial activation. Western blotting of sarkosyl-insoluble tau demonstrated the presence of 2 major tau bands of 64 and 68 kd. No mutations in the microtubule-associated protein tau gene were detected in 2 affected individuals. We propose that 4-repeat tau-immunoreactive GGIs are the neuropathologic hallmark of a distinct sporadic tauopathy with variable clinical presentations that include frontotemporal dementia and occasionally upper motor neuron disease. This type of tauopathy with GGIs expands the group of neurodegenerativedisorders in which oligodendroglial pathology predominates, beyond the synucleinopathy multiple system atrophy disorders.

Genetic Creutzfeldt-Jakob disease associated with the E200K mutation: characterization of a complex proteinopathy

The E200K mutation is the most frequent prion protein gene (PRNP) mutation detected worldwide that is associated with Creutzfeldt-Jakob disease (CJD) and thought to have overlapping features with sporadic CJD, yet detailed neuropathological studies have not been reported. In addition to the prion protein, deposition of tau, α-synuclein, and amyloid-β has been reported in human prion disease. To describe the salient and concomitant neuropathological alterations, we performed a systematic clinical, neuropathological, and biochemical study of 39 individuals carrying the E200K PRNP mutation originating from different European countries. The most frequent clinical symptoms were dementia and ataxia followed by myoclonus and various combinations of further symptoms, including vertical gaze palsy and polyneuropathy. Neuropathological examination revealed relatively uniform anatomical pattern of tissue lesioning, predominating in the basal ganglia and thalamus, and also substantia nigra, while the deposition of disease-associated PrP was more influenced by the codon 129 constellation, including different or mixed types of PrPres detected by immunoblotting. Unique and prominent intraneuronal PrP deposition involving brainstem nuclei was also noted. Systematic examination of protein depositions revealed parenchymal amyloid-β in 53.8%, amyloid angiopathy (Aβ) in 23.1%, phospho-tau immunoreactive neuritic profiles in 92.3%, neurofibrillary degeneration in 38.4%, new types of tau pathology in 33.3%, and Lewy-type α-synuclein pathology in 15.4%. TDP-43 and FUS immunoreactive protein deposits were not observed. This is the first demonstration of intensified and combined neurodegeneration in a genetic prion disease due to a single point mutation, which might become an important model to decipher the molecular interplay between neurodegeneration-associated proteins.

Lewy body variant of Alzheimer's disease: α-synuclein in dystrophic neurites of Aβ plaques

The contribution of α-synuclein accumulation in Alzheimers disease (AD) plaques is currently a matter of scientific debate. In the present study antisera against the N- and C-terminus, the full-length protein and the central so-called non-amyloid component (NAC) domain of the α-synuclein protein were used to address this question in brains of cases with typical AD and of cases with the Lewy body (LB) variant of AD. In typical AD cases, none of the antisera revealed evidence for co-accumulation of α-synuclein with extracellular Aβ peptides in plaques or in dystrophic neurites decorating the plaque core. Interestingly, cases with mixed pathology of the LB variant of AD revealed accumulation of α-synuclein in LBs and in dystrophic neurites of Aβ plaques.

Apolipoprotein E polymorphism in Pick's disease and in Huntington's disease

The polymorphism of apolipoprotein E (apoE) has been recognized as a genetic risk factor in different neurodegenerative disorders, with or without tau protein- related neuropathology, but few published epidemiological data are available as concerns the association of different apoE alleles with two relatively rare forms of dementia, Picks disease (PiD) and Huntingtons disease (HD). In this study the frequency of the apoE4 allele was examined in 36 persons with histopathologically proven PiD and compared with that of the apoE genotype in 28 HD probands and 79 aged healthy controls. The E4 allele was overrepresented selectively in PiD (42%) as compared with the control population (7%). No such association was found for HD probands (9%). This finding lends further support to the hypothesis that the E4 genotype is not an Alzheimers disease specific susceptibility factor, and that it could be present in diverse dementing disorders with tau protein related neuropathology, such as PiD.

Neuropathology of the hippocampus in FTLD-Tau with Pick bodies: a study of the BrainNet Europe Consortium.

G. G. Kovacs, A. J. M. Rozemuller, J. C. van Swieten, E. Gelpi, K. Majtenyi, S. Al‐Sarraj, C. Troakes, I. Bódi, A. King, T. Hortobágyi, M. M. Esiri, O. Ansorge, G. Giaccone, I. Ferrer, T. Arzberger, N. Bogdanovic, T. Nilsson, I. Leisser, I. Alafuzoff, J. W. Ironside, H. Kretzschmar and H. Budka (2013) Neuropathology and Applied Neurobiology39, 166–178

Heroin abuse is characterized by discrete mesolimbic dopamine and opioid abnormalities and exaggerated nuclear receptor-related 1 transcriptional decline with age.

Dysfunction of mesocorticolimbic dopaminergic neurons is considered a common feature of all drugs of abuse, yet few investigations have evaluated the dopamine (DA) system in nonstimulant human abusers. We examined mRNA expression levels of DA transporter (DAT), tyrosine hydroxylase (TH), dopamine D2 receptor, α-synuclein, and nuclear receptor-related 1 (Nurr1) in discrete mesocorticolimbic and nigrostriatal subpopulations of heroin users and control subjects. The chronic use of heroin was significantly associated with decreased DAT mRNA expression localized to the paranigral nucleus (PN) and the mesolimbic division of the ventral tegmental area (VTA) with no alterations in nigrostriatal populations. Consistently, the density of DAT immunoreactivity was significantly reduced in the nucleus accumbens but not in dorsal striatum, mesolimbic and nigrostriatal efferent targets, respectively. Significant alteration of the mRNA expression of Nurr1, a transcription factor that regulates DAT expression, was also confined to the PN. Moreover, the results revealed an exaggerated reduction of Nurr1 expression with age in heroin users (r = −0.8268, p < 0.001 vs controls, r = −0.6204, p = 0.0746). TH and α-synuclein mRNA levels were, in contrast, elevated in the VTA PN in heroin users with no change of the D2 receptor. Evaluating midbrain μ- and κ-opioid receptors, relevant for the action of heroin and regulation of DA neurons, revealed dysregulation of G-protein coupling selective to the VTA PN. Altogether the current findings provide direct neurobiological evidence that midbrain reward circuits have the most prominent DA and opioid impairments in human heroin abusers and that abnormal Nurr1 transcription with opiate use may exacerbate limbic dysfunction with age.

Heroin abuse exaggerates age-related deposition of hyperphosphorylated tau and p62-positive inclusions

The observation of increased hyperphosphorylated tau levels correlating with microglial activation in opiate abusers has been interpreted as predisposition to accelerated Alzheimer disease-related changes. The present study focused on evaluating additional neurodegeneration-related proteins, including α-synuclein and TDP-43, and p62-positive deposits. We performed a systematic mapping of protein deposits in the brains of 27 individuals with documented heroin addiction (age: 19-40 years) and compared with 11 controls (age: 15-40 years). We confirm previous findings that heroin addiction associates with tau hyperphosphorylation in predilection brain areas for aging and Alzheimer disease. Furthermore, we show that this occurs also in areas implicated in the molecular disturbances and in vivo neuronal networks related to heroin abuse. There was, however, no presence of amyloid-beta deposits. We extend previous findings by showing the lack of TDP-43 or α-synuclein pathology and emphasize the independent effect of the duration of drug use on the appearance of age-related p62-positive neuritic profiles. These observations provide unique insights about neuropathological alterations in the brains of young heroin addicts and have implications about brain aging and the influences of environmental and toxic factors.

Beiträge zur Pathologie der subakuten spongiösen Encephalopathie

ZusammenfassungEs werden klinische und pathologische Angaben von fünf an subakuter spongiöser Encephalopathie Verstorbenen beschrieben. Die in vier Fällen durchgeführte EEG-Untersuchung zeigte die für diese Erkrankung charakteristischen Veränderungen.Die Astrocytenveränderungen der Rinde, die der Spongiosität und der Nervenzellveränderungen vorangehen, wurden in wechselndem Ausmaß und Topographie in jedem Fall aufgefunden. In einem Falle standen die Veränderungen der Stammganglien im Vordergrund; da ebenso die klinischen wie auch die pathologischen Merkmale desselben mit den übrigen Fällen wesensgleich waren, wurde der Fall auch zu den spongiösen Encephalopathien gerechnet. Die Astrocytose wird als primäres morphologisches Zeichen, die corticalen spongiosen Veränderungen und die Nervenzelldestruktion hingegen als ihre Folgen aufgefaßt. Die vasculären Faktoren können topographiebestimmende pathogenetische Mitwirkung leisten, ohne eine grundlegende Bedeutung zu haben.SummaryClinico-pathological description of five cases of subacute spongiform encephalopathy. The E.E.G. performed in four cases showed the characteristic pattern of the disease. Alterations of astrocytes in the cerebral cortex preceding the spongy lesions and nerve cell alterations were found in each of the cases in variable intensity and topography. In one case the lesions were accentuated in the basal ganglia. As the clinicopathological features of this observation were the same as in the other cases it was included to the group of spongiform encephalopathies. Astrocytosis is considered as the first morphological sign, cortical spongiform alterations and nerve cell destruction, however, are suggested as its sequelae. Vascular factors probably determine the topography of the lesions, but are of no essential pathogenic importance.