title: Rapidly progressive Alzheimer's disease features distinct structures of amyloid-β.
abstract: Genetic and environmental factors that increase the risk of late-onset Alzheimer disease are now well recognized but the cause of variable progression rates and phenotypes of sporadic Alzheimer's disease is largely unknown. We aimed to investigate the relationship between diverse structural assemblies of amyloid-β and rates of clinical decline in Alzheimer's disease. Using novel biophysical methods, we analysed levels, particle size, and conformational characteristics of amyloid-β in the posterior cingulate cortex, hippocampus and cerebellum of 48 cases of Alzheimer's disease with distinctly different disease durations, and correlated the data with APOE gene polymorphism. In both hippocampus and posterior cingulate cortex we identified an extensive array of distinct amyloid-β42 particles that differ in size, display of N-terminal and C-terminal domains, and conformational stability. In contrast, amyloid-β40 present at low levels did not form a major particle with discernible size, and both N-terminal and C- terminal domains were largely exposed. Rapidly progressive Alzheimer's disease that is associated with a low frequency of APOE e4 allele demonstrates considerably expanded conformational heterogeneity of amyloid-β42, with higher levels of distinctly structured amyloid-β42 particles composed of 30-100 monomers, and fewer particles composed of < 30 monomers. The link between rapid clinical decline and levels of amyloid-β42 with distinct structural characteristics suggests that different conformers may play an important role in the pathogenesis of distinct Alzheimer's disease phenotypes. These findings indicate that Alzheimer's disease exhibits a wide spectrum of amyloid-β42 structural states and imply the existence of prion-like conformational strains.
authors: 1 Department of Pathology, Case Western Reserve University School of Medicine, 2085 Adelbert Rd, Cleveland, OH 44106, USA 2 National Prion Disease Pathology Surveillance Centre, Case Western Reserve University School of Medicine, 2085 Adelbert Rd, Cleveland, OH 44106, USA.
authors: Mark L
authors: ML
authors: Cohen
authors: 1 Department of Pathology, Case Western Reserve University School of Medicine, 2085 Adelbert Rd, Cleveland, OH 44106, USA.
authors: Chae
authors: C
authors: Kim
authors: 1 Department of Pathology, Case Western Reserve University School of Medicine, 2085 Adelbert Rd, Cleveland, OH 44106, USA.
authors: Tracy
authors: T
authors: Haldiman
authors: 1 Department of Pathology, Case Western Reserve University School of Medicine, 2085 Adelbert Rd, Cleveland, OH 44106, USA.
authors: Mohamed
authors: M
authors: ElHag
authors: 3 Department of Neurology, Case Western Reserve University School of Medicine, 2085 Adelbert Rd, Cleveland, OH 44106, USA.
authors: Prachi
authors: P
authors: Mehndiratta
authors: 3 Department of Neurology, Case Western Reserve University School of Medicine, 2085 Adelbert Rd, Cleveland, OH 44106, USA.
authors: Termsarasab
authors: T
authors: Pichet
authors: 3 Department of Neurology, Case Western Reserve University School of Medicine, 2085 Adelbert Rd, Cleveland, OH 44106, USA.
authors: Frances
authors: F
authors: Lissemore
authors: 3 Department of Neurology, Case Western Reserve University School of Medicine, 2085 Adelbert Rd, Cleveland, OH 44106, USA.
authors: Michelle
authors: M
authors: Shea
authors: 1 Department of Pathology, Case Western Reserve University School of Medicine, 2085 Adelbert Rd, Cleveland, OH 44106, USA 2 National Prion Disease Pathology Surveillance Centre, Case Western Reserve University School of Medicine, 2085 Adelbert Rd, Cleveland, OH 44106, USA.
authors: Yvonne
authors: Y
authors: Cohen
authors: 1 Department of Pathology, Case Western Reserve University School of Medicine, 2085 Adelbert Rd, Cleveland, OH 44106, USA 2 National Prion Disease Pathology Surveillance Centre, Case Western Reserve University School of Medicine, 2085 Adelbert Rd, Cleveland, OH 44106, USA.
authors: Wei
authors: W
authors: Chen
authors: 1 Department of Pathology, Case Western Reserve University School of Medicine, 2085 Adelbert Rd, Cleveland, OH 44106, USA 2 National Prion Disease Pathology Surveillance Centre, Case Western Reserve University School of Medicine, 2085 Adelbert Rd, Cleveland, OH 44106, USA.
authors: Janis
authors: J
authors: Blevins
authors: 3 Department of Neurology, Case Western Reserve University School of Medicine, 2085 Adelbert Rd, Cleveland, OH 44106, USA 4 Department of Psychiatry, Case Western Reserve University School of Medicine, 2085 Adelbert Rd, Cleveland, OH 44106, USA.
authors: Brian S
authors: BS
authors: Appleby
authors: 5 Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, 2085 Adelbert Rd, Cleveland, OH 44106, USA.
authors: Krystyna
authors: K
authors: Surewicz
authors: 5 Department of Physiology and Biophysics, Case Western Reserve University School of Medicine, 2085 Adelbert Rd, Cleveland, OH 44106, USA.
authors: Witold K
authors: WK
authors: Surewicz
authors: 3 Department of Neurology, Case Western Reserve University School of Medicine, 2085 Adelbert Rd, Cleveland, OH 44106, USA 4 Department of Psychiatry, Case Western Reserve University School of Medicine, 2085 Adelbert Rd, Cleveland, OH 44106, USA.
authors: Martha
authors: M
authors: Sajatovic
authors: 3 Department of Neurology, Case Western Reserve University School of Medicine, 2085 Adelbert Rd, Cleveland, OH 44106, USA.
authors: Curtis
authors: C
authors: Tatsuoka
authors: 1 Department of Pathology, Case Western Reserve University School of Medicine, 2085 Adelbert Rd, Cleveland, OH 44106, USA.
authors: Shulin
authors: S
authors: Zhang
authors: 6 Department of Epidemiology and Biostatistics, Case Western Reserve University School of Medicine, 2085 Adelbert Rd, Cleveland, OH 44106, USA.
authors: Ping
authors: P
authors: Mayo
authors: 6 Department of Epidemiology and Biostatistics, Case Western Reserve University School of Medicine, 2085 Adelbert Rd, Cleveland, OH 44106, USA.
authors: Mariusz
authors: M
authors: Butkiewicz
authors: 6 Department of Epidemiology and Biostatistics, Case Western Reserve University School of Medicine, 2085 Adelbert Rd, Cleveland, OH 44106, USA.
authors: Jonathan L
authors: JL
authors: Haines
authors: 3 Department of Neurology, Case Western Reserve University School of Medicine, 2085 Adelbert Rd, Cleveland, OH 44106, USA.
authors: Alan J
authors: AJ
authors: Lerner
authors: 1 Department of Pathology, Case Western Reserve University School of Medicine, 2085 Adelbert Rd, Cleveland, OH 44106, USA 2 National Prion Disease Pathology Surveillance Centre, Case Western Reserve University School of Medicine, 2085 Adelbert Rd, Cleveland, OH 44106, USA 3 Department of Neurology, Case Western Reserve University School of Medicine, 2085 Adelbert Rd, Cleveland, OH 44106, USA jiri.safar@case.edu.
authors: Jiri G
authors: JG
authors: Safar
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000544:Alzheimer Disease / Q000235:genetics* / Q000473:pathology*; D016229:Amyloid beta-Peptides / Q000235:genetics*; D015331:Cohort Studies; D018450:Disease Progression; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D010446:Peptide Fragments / Q000235:genetics*; D013997:Time Factors
chemical_list: D016229:Amyloid beta-Peptides; D010446:Peptide Fragments; C075222:amyloid beta-protein (1-42)
keywords: Alzheimer; progression rate; structure; β-amyloid