The amyloid cascade hypothesis postulates that extracellular deposits of amyloid β (Aβ) are the primary and initial cause leading to the full development of Alzheimer's disease (AD) with intracellular neurofibrillary tangles; however, the details of this mechanism have not been fully described until now. Our preliminary data, coming from our day-to-day neuropathology practice, show that the primary location of the hyperphosphorylated tau protein is in the vicinity of the cell membrane of dystrophic neurites. This observation inspired us to formulate a hypothesis that presumes an interaction between low-density lipoprotein receptor-related protein 1 (LRP1) and fibrillar aggregates of, particularly, Aβ42 anchored at the periphery of neuritic plaques, making internalization of the LRP1-Aβ42 complex infeasible and, thus, causing membrane dysfunction, leading to the tauopathy characterized by intracellular accumulation and hyperphosphorylation of the tau protein. Understanding AD as a membrane dysfunction tauopathy may draw attention to new treatment approaches not only targeting Aβ42 production but also, perhaps paradoxically, preventing the formation of LRP1-Aβ42.

• Klíčová slova
• Alzheimer’s disease, amyloid β, membrane dysfunction, tauopathy,
• MeSH
• Alzheimerova nemoc * metabolismus   patologie   etiologie   MeSH
• amyloidní beta-protein * metabolismus   MeSH
• buněčná membrána metabolismus   MeSH
• fosforylace MeSH
• lidé MeSH
• peptidové fragmenty metabolismus   MeSH
• protein 1 související s LDL-receptory * metabolismus   MeSH
• proteiny tau * metabolismus   MeSH
• tauopatie * metabolismus   patologie   etiologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• přehledy MeSH
• Názvy látek
• amyloidní beta-protein * MeSH
• LRP1 protein, human MeSH Prohlížeč
• peptidové fragmenty MeSH
• protein 1 související s LDL-receptory * MeSH
• proteiny tau * MeSH

Gerstmann-Sträussler-Scheinker syndrome (GSS) is a hereditary neurodegenerative disease characterized by extracellular aggregations of pathological prion protein (PrP) forming characteristic plaques. Our study aimed to evaluate the micromorphology and protein composition of these plaques in relation to age, disease duration, and co-expression of other pathogenic proteins related to other neurodegenerations. Hippocampal regions of nine clinically, neuropathologically, and genetically confirmed GSS subjects were investigated using immunohistochemistry and multichannel confocal fluorescent microscopy. Most pathognomic prion protein plaques were small (2-10 µm), condensed, globous, and did not contain any of the other investigated proteinaceous components, particularly dystrophic neurites. Equally rare (in two cases out of nine) were plaques over 50 µm having predominantly fibrillar structure and exhibit the presence of dystrophic neuritic structures; in one case, the plaques also included bulbous dystrophic neurites. Co-expression with hyperphosphorylated protein tau protein or amyloid beta-peptide (Aβ) in GSS PrP plaques is generally a rare observation, even in cases with comorbid neuropathology. The dominant picture of the GSS brain is small, condensed plaques, often multicentric, while presence of dystrophic neuritic changes accumulating hyperphosphorylated protein tau or Aβ in the PrP plaques are rare and, thus, their presence probably constitutes a trivial observation without any relationship to GSS development and progression.

• Klíčová slova
• Gerstmann–Sträussler–Scheinker syndrome, PrP, co-expression, plaques,
• MeSH
• dospělí MeSH
• Gerstmannova-Strausslerova-Scheinkerova nemoc * genetika   metabolismus   patologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• missense mutace * MeSH
• patologická konformace proteinů * genetika   metabolismus   patologie   MeSH
• prionová bílkovina * genetika   metabolismus   MeSH
• senioři MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• srovnávací studie MeSH
• Názvy látek
• prionová bílkovina * MeSH

Alzheimer's disease (AD) and sporadic Creutzfeldt-Jakob disease (sCJD) are both characterized by extracellular pathologically conformed aggregates of amyloid proteins-amyloid β-protein (Aβ) and prion protein (PrPSc), respectively. To investigate the potential morphological colocalization of Aβ and PrPSc aggregates, we examined the hippocampal regions (archicortex and neocortex) of 20 subjects with confirmed comorbid AD and sCJD using neurohistopathological analyses, immunohistochemical methods, and confocal fluorescent microscopy. Our data showed that extracellular Aβ and PrPSc aggregates tended to be, in most cases, located separately, and "compound" plaques were relatively rare. We observed PrPSc plaque-like structures in the periphery of the non-compact parts of Aβ plaques, as well as in tau protein-positive dystrophic structures. The AD ABC score according to the NIA-Alzheimer's association guidelines, and prion protein subtype with codon 129 methionine-valine (M/V) polymorphisms in sCJD, while representing key characteristics of these diseases, did not correlate with the morphology of the Aβ/PrPSc co-aggregates. However, our data showed that PrPSc aggregation could dominate during co-aggregation with non-compact Aβ in the periphery of Aβ plaques.

• Klíčová slova
• Alzheimer’s disease, Aβ, Creutzfeldt–Jakob disease, colocalization, confocal microscopy, plaques, prion protein, tau protein,
• MeSH
• Alzheimerova nemoc patologie   MeSH
• amyloidní beta-protein genetika   metabolismus   MeSH
• amyloidní plaky patologie   MeSH
• Creutzfeldtova-Jakobova nemoc patologie   MeSH
• extracelulární prostor chemie   MeSH
• jednonukleotidový polymorfismus genetika   MeSH
• kodon genetika   MeSH
• komorbidita MeSH
• lidé středního věku MeSH
• lidé MeSH
• mozek patologie   MeSH
• neurony patologie   MeSH
• pilotní projekty MeSH
• proteinové agregáty * MeSH
• proteiny tau metabolismus   MeSH
• PrPSc proteiny genetika   metabolismus   MeSH
• senioři nad 80 let MeSH
• senioři 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
• Názvy látek
• amyloidní beta-protein MeSH
• kodon MeSH
• proteinové agregáty * MeSH
• proteiny tau MeSH
• PrPSc proteiny MeSH