In Alzheimer's disease (AD), two mutually exclusive amino-terminal-dependent conformations have been reported to occur during the aggregation of Tau protein into neurofibrillary tangles (NFTs). An early conformation of full-length Tau, involving the bending of the amino terminus over the third repeated domain, is recognized by the Alz-50 antibody, followed by a second conformation recognized by Tau-66 antibody that depends on the folding of the proline-rich region over the third repeated domain in a molecule partially truncated at the amino- and carboxyl-termini. α-1-antichymotrypsin (ACT) is an acute phase serum glycoprotein that accumulates abnormally in the brain of AD patients, and since it is considered to promote the in vitro and in vivo aggregation of amyloid-β, we here seek further evidence that ACT may also contribute to the abnormal aggregation of Tau in AD. By analyzing brain samples from a population of AD cases under immunofluorescence and high-resolution confocal microscopy, we demonstrate here the abundant expression of ACT in hippocampal neurons, visualized as a granular diffuse accumulation, frequently reaching the nuclear compartment. In a significant number of these neurons, intracellular NFTs composed of abnormally phosphorylated and truncated Tau at Asp421 were also observed to coexist in separated regions of the cytoplasm. However, we found strong colocalization between ACT and diffuse aggregates of Tau-66-positive granules, which was not observed with Alz-50 antibody. These results suggest that ACT may play a role during the development of Tau conformational changes facilitating its aggregation during the formation of the neurofibrillary pathology in AD.
In Alzheimer's disease, tau protein undergoes post-translational modifications including hyperphosphorylation and truncation, which promotes two major conformational changes associated with progressive N-terminal folding. Along with the development of the disease, tau ubiquitination was previously shown to emerge in the early and intermediate stages of the disease, which is closely associated with early tau truncation at aspartic acid 421, but not with a subsequently truncated tau molecule at glutamic acid 391. In the same group of cases, using multiple immunolabeling and confocal microscopy, a possible relationship between the ubiquitin-targeting of tau and the progression of conformational changes adopted by the N-terminus of this molecule was further studied. A comparable number of neurofibrillary tangles was found displaying ubiquitin, an early conformation recognized by the Alz-50 antibody, and a phosphorylation. However, a more reduced number of neurofibrillary tangles were immunoreactive to Tau-66 antibody, a late tau conformational change marker. When double-labeling profiles of neurofibrillary tangles were assessed, ubiquitination was clearly demonstrated in tau molecules undergoing early N-terminal folding, but was barely observed in late conformational changes of the N-terminus adopted by tau. The same pattern of colocalization was visualized in neuritic pathology. Overall, these results indicate that a more intact conformation of the N-terminus of tau may facilitate tau ubiquitination, but this modification may not occur in a late truncated and more compressed folding of the N-terminus of the tau molecule.
- MeSH
- Alzheimerova nemoc metabolismus patologie MeSH
- konformace proteinů MeSH
- lidé středního věku MeSH
- lidé MeSH
- mozek metabolismus patologie MeSH
- neurofibrilární klubka chemie patologie MeSH
- proteiny tau chemie metabolismus MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ubikvitinace fyziologie MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Rozsáhlá literatura posledních 40 let obviňuje mozkový amyloid jako jeden z kauzálních faktorů stařecké demence. Amyloid je tak tradován spolu s fibrilárními intracelulárními inkluzemi τ-proteinu jako původce specifické Alzheimerovy nemoci. Poté, co jsme byli dlouhá desetiletí závislí na amyloidní detekci v pitevních vzorcích, dosahuje dnes použití radioaktivních ligandů cestou pozitronové emisní tomografie (PET) vysoce instruktivních nálezů in vivo. Poznání souvislostí mezi duševním výkonem a intenzitou amyloidních depozit dostalo tedy nový rozměr. Poskytujeme přehled metod a jejich závěrů, které přinášejí nové světlo do mechanizmů stárnoucího mozku: histologické vlastnosti amyloidu, techniky a výtěžnost jeho detekce v PET, vztah denzity amyloidu k denzitě neurofibrilárních klubíček, vztah k intenzitě tkáňového metabolizmu a atrofii, dynamiku výskytu vzhledem k věku probanda a korelační studie mezi amyloidem a duševním výkonem. Podaný výklad zpochybňuje kauzální roli amyloidu v duševní deterioraci seniorů, a tím i jeden z pilířů tzv. Alzheimerovy nemoci.
Extensive literature from the past 40 years accuses brain amyloid as one of the causal factors of senile dementia. Amyloid is considered, together with intracellular inclusions of τ-protein, as the originator for a specific Alzheimer‘s disease. After being dependent for many decades on amyloid detection only in autopsy specimens, the application of radioactive ligands using positron emission tomography (PET) currently achieves highly informative in vivo findings. The recognition of relations between mental acuity and the intensity of amyloid deposits has thus obtained a new dimension. We are providing a review of methods and their conclusions which shed light onto the mechanisms of brain ageing: histological properties of amyloid, techniques and the yield of its detection in PET, relation of amyloid density to that of neurofibrillary tangles, its relation to tissue metabolism and atrophy, dynamics of amyloid presence according to age and correlative studies between amyloid and mental efectivity. The given interpretation puts doubt on the causal role of amyloid in the psychic deterioration of seniors and thus also on one of the pillars of the so-called Alzheimer‘s disease.
- MeSH
- Alzheimerova nemoc etiologie patologie MeSH
- amyloid * fyziologie toxicita MeSH
- amyloidní plaky dějiny patologie MeSH
- demence * etiologie patologie MeSH
- klinické zkoušky jako téma MeSH
- lidé MeSH
- mozek diagnostické zobrazování metabolismus patologie MeSH
- neurofibrilární klubka patologie MeSH
- pozitronová emisní tomografie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- práce podpořená grantem MeSH
- přehledy MeSH
We report a 44-year-old woman, with a family history of early-onset dementia, presenting with primary progressive aphasia. This clinically variable syndrome has multiple underlying pathologies, and correlations between clinical manifestations and postmortem neuropathologic findings are controversial. Our patient suffered worsening language impairment with major word-finding difficulties but preserved comprehension. She also developed episodic memory impairment. Her condition progressed to dementia with behavioral changes. Magnetic resonance imaging showed early left perisylvian and bitemporal atrophy. The patient died shortly afterward from colon cancer. Neuropathologic examination revealed advanced early-onset Alzheimer and Lewy body disease, plus a clinically nonrelevant metastasis of her colon cancer in her left parietal lobe. Genetic examination revealed a p.Glu184Asp mutation in the presenilin1 gene. Our findings confirm the importance of a thorough appreciation for the clinical and neuropathologic correlations in patients with atypical neurodegenerative dementias.
- MeSH
- Alzheimerova nemoc komplikace diagnóza genetika patologie MeSH
- demence s Lewyho tělísky komplikace diagnóza genetika patologie MeSH
- dospělí MeSH
- fatální výsledek MeSH
- lidé MeSH
- magnetická rezonanční tomografie MeSH
- mozek patologie MeSH
- neurity patologie MeSH
- neurofibrilární klubka patologie MeSH
- neuropsychologické testy MeSH
- presenilin-1 genetika MeSH
- primární progresivní afázie diagnóza etiologie patologie MeSH
- Check Tag
- dospělí MeSH
- lidé MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- kazuistiky MeSH
Alzheimer's disease (AD) is the most frequent cause of dementia. Misfolded protein pathological hallmarks of AD are brain deposits of amyloid-β (Aβ) plaques and phosphorylated tau neurofibrillary tangles. However, doubts about the role of Aβ in AD pathology have been raised as Aβ is a common component of extracellular brain deposits found, also by in vivo imaging, in non-demented aged individuals. It has been suggested that some individuals are more prone to Aβ neurotoxicity and hence more likely to develop AD when aging brains start accumulating Aβ plaques. Here, we applied genome-wide transcriptomic profiling of lymphoblastoid cells lines (LCLs) from healthy individuals and AD patients for identifying genes that predict sensitivity to Aβ. Real-time PCR validation identified 3.78-fold lower expression of RGS2 (regulator of G-protein signaling 2; P=0.0085) in LCLs from healthy individuals exhibiting high vs low Aβ sensitivity. Furthermore, RGS2 showed 3.3-fold lower expression (P=0.0008) in AD LCLs compared with controls. Notably, RGS2 expression in AD LCLs correlated with the patients' cognitive function. Lower RGS2 expression levels were also discovered in published expression data sets from postmortem AD brain tissues as well as in mild cognitive impairment and AD blood samples compared with controls. In conclusion, Aβ sensitivity phenotyping followed by transcriptomic profiling and published patient data mining identified reduced peripheral and brain expression levels of RGS2, a key regulator of G-protein-coupled receptor signaling and neuronal plasticity. RGS2 is suggested as a novel AD biomarker (alongside other genes) toward early AD detection and future disease modifying therapeutics.
- MeSH
- Alzheimerova nemoc diagnóza genetika patologie MeSH
- amyloidní beta-protein genetika MeSH
- amyloidní plaky genetika patologie MeSH
- buněčné linie MeSH
- časná diagnóza MeSH
- celogenomová asociační studie * MeSH
- data mining * MeSH
- exprese genu genetika MeSH
- fenotyp MeSH
- genetické asociační studie MeSH
- genetické markery genetika MeSH
- lidé MeSH
- mozek patologie MeSH
- neurofibrilární klubka genetika patologie MeSH
- proteiny RGS genetika MeSH
- senioři MeSH
- stanovení celkové genové exprese * MeSH
- výpočetní biologie MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Alzheimer's disease (AD) involves the propagation of filaments of tau protein throughout the cerebral cortex. Imaging tau filaments and oligomers in human brain at high resolution would help contribute insight into the mechanism and progression of tauopathic diseases. STED microscopy is a nano-scale imaging technique and we aimed to test the abilities of this method for resolving tau structures within human brain. Using autopsied 50μm AD brain sections, we demonstrate that STED microscopy can resolve immunolabelled tau filaments at 77nm resolution. Ribbon-like tau filaments imaged by STED appeared smooth along their axis with limited axial undulations. STED also resolved 70-80nm wide tau puncta. Of the fluorophores tested, STAR635p was optimal for STED imaging in this tissue. This was in part due to brain tissue autofluorescence within the lower wavelength ranges (488-590nm). Further, the stability and minimal photobleaching of STAR635p allowed STED z-stacks of neurons packed with tau filaments (neurofibrillary tangles) to be collated. There was no loss of x-y image resolution of individual tau filaments through the 20μm z-stack. This demonstrates that STED can contribute to nano-scale analysis and characterisation of pathologies within banked human autopsied brain tissue. Resolving tau structures at this level of resolution provides promising avenues for understanding mechanisms of pathology propagation in the different tauopathies as well as illuminating what contributes to disease heterogeneity.
- MeSH
- Alzheimerova nemoc diagnostické zobrazování patologie MeSH
- barvení a značení MeSH
- lidé MeSH
- neurofibrilární klubka patologie ultrastruktura MeSH
- optické zobrazování MeSH
- proteiny tau chemie ultrastruktura MeSH
- šedá hmota diagnostické zobrazování patologie MeSH
- zobrazování trojrozměrné MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Dementia with Lewy bodies (DLB) is characterized by preserved whole brain and medial temporal lobe volumes compared with Alzheimer's disease dementia (AD) on magnetic resonance imaging. However, frequently coexistent AD-type pathology may influence the pattern of regional brain atrophy rates in DLB patients. We investigated the pattern and magnitude of the atrophy rates from 2 serial MRIs in autopsy-confirmed DLB patients (n = 20) and mixed DLB/AD patients (n = 22), compared with AD (n = 30) and elderly nondemented control subjects (n = 15), followed antemortem. DLB patients without significant AD-type pathology were characterized by lower global and regional rates of atrophy, similar to control subjects. The mixed DLB/AD patients displayed greater atrophy rates in the whole brain, temporoparietal cortices, hippocampus and amygdala, and ventricle expansion, similar to AD patients. In the DLB and DLB/AD patients, the atrophy rates correlated with Braak neurofibrillary tangle stage, cognitive decline, and progression of motor symptoms. Global and regional atrophy rates are associated with AD-type pathology in DLB, and these rates can be used as biomarkers of AD progression in patients with LB pathology.
- MeSH
- Alzheimerova nemoc diagnóza patologie MeSH
- amygdala patologie MeSH
- atrofie MeSH
- biologické markery MeSH
- demence s Lewyho tělísky patologie psychologie MeSH
- hipokampus patologie MeSH
- kognice MeSH
- lidé MeSH
- magnetická rezonanční tomografie MeSH
- mozek patologie MeSH
- neurofibrilární klubka patologie MeSH
- pitva MeSH
- progrese nemoci MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- spánkový lalok patologie MeSH
- temenní lalok patologie MeSH
- velikost orgánu MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
Alzheimer´s disease (AD) is a neurodegenerative disorder with no known cure and rapid rise in incidence. The predominant cognitive impairment is currently treated using cognitive enhancers like cholinesterase inhibitors. The two molecular hallmarks of AD are amyloid plaques created from an amyloid precursor protein and hyperphosphorylated tau protein that is deposited as neurofibrillary tangles inside neurons. A number of pathological mechanisms follow or precede these formations. Alteration in mitochondrial function and deposition of heavy metals are reported. The disease progression is enhanced by oxidative stress. However, the role of oxidative stress is not universally accepted. The current review covers and discusses the basic evidence and role of oxidative stress in AD development.
- MeSH
- Alzheimerova nemoc metabolismus patologie MeSH
- amyloidní plaky metabolismus patologie MeSH
- amyloidový prekurzorový protein beta metabolismus MeSH
- lidé MeSH
- mitochondrie metabolismus patologie MeSH
- neurofibrilární klubka metabolismus patologie MeSH
- oxidační stres * MeSH
- proteiny tau metabolismus MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- přehledy MeSH
Truncated tau protein at Asp(421) is associated with neurofibrillary pathology in Alzheimer disease (AD); however, little is known about its presence in the form of nonfibrillary aggregates. Here, we report immunohistochemical staining of the Tau-C3 antibody, which recognizes Asp(421)-truncated tau, in a group of AD cases with different extents of cognitive impairment. In the hippocampus, we found distinct nonfibrillary aggregates of Asp(421)-truncated tau. Unlike Asp(421)-composed neurofibrillary tangles, however, these nonfibrillary pathologies did not increase significantly with respect to the Braak staging and, therefore, make no significant contribution to cognitive impairment. On the other hand, despite in vitro evidence that caspase-3 cleaves monomeric tau at Asp(421), to date, this truncation has not been demonstrated to be executed by this protease in polymeric tau entities. We determined that Asp(421) truncation can be produced by caspase-3 in oligomeric and multimeric complexes of recombinant full-length tau in isolated native tau filaments in vitro and in situ in neurofibrillary tangles analyzed in fresh brain slices from AD cases. Our data suggest that generation of this pathologic Asp(421) truncation of tau in long-lasting fibrillary structures may produce further permanent toxicity for neurons in the brains of patients with AD.
- MeSH
- Alzheimerova nemoc patologie MeSH
- chloromethylketony aminokyselin farmakologie MeSH
- elektronová mikroskopie MeSH
- kaspasa 3 metabolismus farmakologie MeSH
- kyselina aspartová metabolismus MeSH
- lidé MeSH
- molekulová hmotnost MeSH
- mozek metabolismus patologie ultrastruktura MeSH
- neurofibrilární klubka metabolismus patologie ultrastruktura MeSH
- neurofibrily metabolismus patologie ultrastruktura MeSH
- neuroprotektivní látky farmakologie MeSH
- oligopeptidy farmakologie MeSH
- proteiny tau účinky léků metabolismus ultrastruktura MeSH
- senioři nad 80 let MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
