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.

• Keywords
• Alzheimer’s disease, amyloid β, membrane dysfunction, tauopathy,
• MeSH
• Alzheimer Disease * metabolism   pathology   etiology   MeSH
• Amyloid beta-Peptides * metabolism   MeSH
• Cell Membrane metabolism   MeSH
• Phosphorylation MeSH
• Humans MeSH
• Peptide Fragments metabolism   MeSH
• Low Density Lipoprotein Receptor-Related Protein-1 * metabolism   MeSH
• tau Proteins * metabolism   MeSH
• Tauopathies * metabolism   pathology   etiology   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• Amyloid beta-Peptides * MeSH
• LRP1 protein, human MeSH Browser
• Peptide Fragments MeSH
• Low Density Lipoprotein Receptor-Related Protein-1 * MeSH
• tau Proteins * 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.

• Keywords
• Gerstmann–Sträussler–Scheinker syndrome, PrP, co-expression, plaques,
• MeSH
• Adult MeSH
• Gerstmann-Straussler-Scheinker Disease * genetics   metabolism   pathology   MeSH
• Middle Aged MeSH
• Humans MeSH
• Mutation, Missense * MeSH
• Protein Aggregation, Pathological * genetics   metabolism   pathology   MeSH
• Prion Proteins * genetics   metabolism   MeSH
• Aged MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Comparative Study MeSH
• Names of Substances
• Prion Proteins * 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.

• Keywords
• Alzheimer’s disease, Aβ, Creutzfeldt–Jakob disease, colocalization, confocal microscopy, plaques, prion protein, tau protein,
• MeSH
• Alzheimer Disease pathology   MeSH
• Amyloid beta-Peptides genetics   metabolism   MeSH
• Plaque, Amyloid pathology   MeSH
• Creutzfeldt-Jakob Syndrome pathology   MeSH
• Extracellular Space chemistry   MeSH
• Polymorphism, Single Nucleotide genetics   MeSH
• Codon genetics   MeSH
• Comorbidity MeSH
• Middle Aged MeSH
• Humans MeSH
• Brain pathology   MeSH
• Neurons pathology   MeSH
• Pilot Projects MeSH
• Protein Aggregates * MeSH
• tau Proteins metabolism   MeSH
• PrPSc Proteins genetics   metabolism   MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Amyloid beta-Peptides MeSH
• Codon MeSH
• Protein Aggregates * MeSH
• tau Proteins MeSH
• PrPSc Proteins MeSH