Distinct conformers of amyloid beta accumulate in the neocortex of patients with rapidly progressive Alzheimer's disease
2021; Elsevier BV; Volume: 297; Issue: 5 Linguagem: Inglês
10.1016/j.jbc.2021.101267
ISSN1083-351X
AutoresHe Liu, Chae Kim, Tracy Haldiman, Christina J. Sigurdson, Sofie Nyström, K. Peter R. Nilsson, Mark L. Cohen, Thomas Wısnıewskı, Per Hammarström, Jiri Safar,
Tópico(s)Cholinesterase and Neurodegenerative Diseases
ResumoAmyloid beta (Aβ) deposition in the neocortex is a major hallmark of Alzheimer's disease (AD), but the extent of deposition does not readily explain phenotypic diversity and rate of disease progression. The prion strain–like model of disease heterogeneity suggests the existence of different conformers of Aβ. We explored this paradigm using conformation-dependent immunoassay (CDI) for Aβ and conformation-sensitive luminescent conjugated oligothiophenes (LCOs) in AD cases with variable progression rates. Mapping the Aβ conformations in the frontal, occipital, and temporal regions in 20 AD patients with CDI revealed extensive interindividual and anatomical diversity in the structural organization of Aβ with the most significant differences in the temporal cortex of rapidly progressive AD. The fluorescence emission spectra collected in situ from Aβ plaques in the same regions demonstrated considerable diversity of spectral characteristics of two LCOs—quatroformylthiophene acetic acid and heptaformylthiophene acetic acid. Heptaformylthiophene acetic acid detected a wider range of Aβ deposits, and both LCOs revealed distinct spectral attributes of diffuse and cored plaques in the temporal cortex of rapidly and slowly progressive AD and less frequent and discernible differences in the frontal and occipital cortex. These and CDI findings indicate a major conformational diversity of Aβ accumulating in the neocortex, with the most notable differences in temporal cortex of cases with shorter disease duration, and implicate distinct Aβ conformers (strains) in the rapid progression of AD. Amyloid beta (Aβ) deposition in the neocortex is a major hallmark of Alzheimer's disease (AD), but the extent of deposition does not readily explain phenotypic diversity and rate of disease progression. The prion strain–like model of disease heterogeneity suggests the existence of different conformers of Aβ. We explored this paradigm using conformation-dependent immunoassay (CDI) for Aβ and conformation-sensitive luminescent conjugated oligothiophenes (LCOs) in AD cases with variable progression rates. Mapping the Aβ conformations in the frontal, occipital, and temporal regions in 20 AD patients with CDI revealed extensive interindividual and anatomical diversity in the structural organization of Aβ with the most significant differences in the temporal cortex of rapidly progressive AD. The fluorescence emission spectra collected in situ from Aβ plaques in the same regions demonstrated considerable diversity of spectral characteristics of two LCOs—quatroformylthiophene acetic acid and heptaformylthiophene acetic acid. Heptaformylthiophene acetic acid detected a wider range of Aβ deposits, and both LCOs revealed distinct spectral attributes of diffuse and cored plaques in the temporal cortex of rapidly and slowly progressive AD and less frequent and discernible differences in the frontal and occipital cortex. These and CDI findings indicate a major conformational diversity of Aβ accumulating in the neocortex, with the most notable differences in temporal cortex of cases with shorter disease duration, and implicate distinct Aβ conformers (strains) in the rapid progression of AD. The hallmark of sporadic Alzheimer's disease (sAD) is the accumulation of misfolded aggregates of amyloid beta (Aβ) and hyperphosphorylated tau forming neurofibrillary tangles (NFTs) (1Braak H. 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The existence of Aβ strains and their potential for driving phenotypic heterogeneity in Alzheimer's disease.Acta Neuropathol. 2021; 142: 17-39Crossref PubMed Scopus (11) Google Scholar). Here, we compared the fluorescence spectral analysis of two chemically different LCOs upon binding to Aβ plaque morphotypes in three anatomical regions of rpAD and slowly progressive AD (spAD) cases and then correlated the data with CDI and immunohistochemistry using conformation-sensitive antibodies. The results demonstrated extensive molecular landscape for distinct conformers of Aβ in diverse clinical phenotypes and major interindividual variability in Aβ structural organization. The LCOs were able to corroborate this conclusion in different plaque morphotypes formed by Aβ with different conformations directly in situ in the brain cortex sections of patients with AD. The rapidly progressive cases of AD were initially referred to the National Prion Disease Pathology Surveillance Center (NPDPSC) as rapidly progressive or atypical dementia with working diagnosis of probable prion diseases, but these cases subsequently failed to confirm neuropathologic or genetic evidence for prion disease after prion protein (PRNP) gene sequencing and instead established definite neuropathological diagnosis of AD according to the National Institutes of Aging—Alzheimer's Association (NIA-AA) (5Schellenberg G.D. Montine T.J. The genetics and neuropathology of Alzheimer's disease.Acta Neuropathol. 2012; 124: 305-323Crossref PubMed Scopus (169) Google Scholar) (Table 1). From 186 cases with an identifiable disease starting date which we obtained from detailed clinical records and semistructured telephone interviews with patients and/or caregivers at the time of referral, we selected 32 cases with the available frozen frontal, occipital, and temporal cortex (17Cohen M.L. Kim C. Haldiman T. ElHag M. Mehndiratta P. Pichet T. Lissemore F. Shea M. Cohen Y. Chen W. Blevins J. Appleby B.S. Surewicz K. Surewicz W.K. Sajatovic M. et al.Rapidly progressive Alzheimer's disease features distinct structures of amyloid-β.Brain. 2015; 138: 1009-1022Crossref PubMed Scopus (117) Google Scholar, 37Pillai J.A. Appleby B.S. Safar J. Leverenz J.B. Rapidly progressive Alzheimer's disease in two distinct autopsy cohorts.J. Alzheimers Dis. 2018; 64: 973-980Crossref PubMed Scopus (10) Google Scholar, 38Pillai J.A. Bonner-Jackson A. Bekris L.M. Safar J. Bena J. Leverenz J.B. Highly elevated cerebrospinal fluid total tau level reflects higher likelihood of non-amnestic subtype of Alzheimer's disease.J. Alzheimers Dis. 2019; 70: 1051-1058Crossref PubMed Scopus (13) Google Scholar). Our second cohort consisted of 34 classical AD cases collected at New York University (NYU) Alzheimer Disease Center (see the Experimental procedures section) that matched our previously reported Case Western Reserve University cohort (17Cohen M.L. Kim C. Haldiman T. ElHag M. Mehndiratta P. Pichet T. Lissemore F. Shea M. Cohen Y. Chen W. Blevins J. Appleby B.S. Surewicz K. Surewicz W.K. Sajatovic M. et al.Rapidly progressive Alzheimer's disease features distinct structures of amyloid-β.Brain. 2015; 138: 1009-1022Crossref PubMed Scopus (117) Google Scholar, 37Pillai J.A. Appleby B.S. Safar J. Leverenz J.B. Rapidly progressive Alzheimer's disease in two distinct autopsy cohorts.J. Alzheimers Dis. 2018; 64: 973-980Crossref PubMed Scopus (10) Google Scholar) and progression rates and demographics distribution in the National Alzheimer's Coordinating Center dataset and hereafter was referred to as spAD (Fig. 1, A and B and Table 1) (17Cohen M.L. Kim C. Haldiman T. ElHag M. Mehndiratta P. Pichet T. Lissemore F. Shea M. Cohen Y. Chen W. Blevins J. Appleby B.S. Surewicz K. Surewicz W.K. Sajatovic M. et al.Rapidly progressive Alzheimer's disease features distinct structures of amyloid-β.Brain. 2015; 138: 1009-1022Crossref PubMed Scopus (117) Google Scholar, 37Pillai J.A. Appleby B.S. Safar J. Leverenz J.B. Rapidly progressive Alzheimer's disease in two distinct autopsy cohorts.J. Alzheimers Dis. 2018; 64: 973-980Crossref PubMed Scopus (10) Google Scholar, 38Pillai J.A. Bonner-Jackson A. Bekris L.M. Safar J. Bena J. Leverenz J.B. Highly elevated cerebrospinal fluid total tau level reflects higher likelihood of non-amnestic subtype of Alzheimer's disease.J. Alzheimers Dis. 2019; 70: 1051-1058Crossref PubMed Scopus (13) Google Scholar). The faster progression in rpAD cases was associated with younger age at death, which agreed with findings from our previous studies (17Cohen M.L. Kim C. Haldiman T. ElHag M. Mehndiratta P. Pichet T. Lissemore F. Shea M. Cohen Y. Chen W. Blevins J. Appleby B.S. Surewicz K. Surewicz W.K. Sajatovic M. et al.Rapidly progressive Alzheimer's disease features distinct structures of amyloid-β.Brain. 2015; 138: 1009-1022Crossref PubMed Scopus (117) Google Scholar, 37Pillai J.A. Appleby B.S. Safar J. Leverenz J.B. Rapidly progressive Alzheimer's disease in two distinct autopsy cohorts.J. Alzheimers Dis. 2018; 64: 973-980Crossref PubMed Scopus (10) Google Scholar, 38Pillai J.A. Bonner-Jackson A. Bekris L.M. Safar J. Bena J. Leverenz J.B. Highly elevated cerebrospinal fluid total tau level reflects higher likelihood of non-amnestic subtype of Alzheimer's disease.J. Alzheimers Dis. 2019; 70: 1051-1058Crossref PubMed Scopus (13) Google Scholar) and with data from prion centers in Japan and Europe (39Schmidt C. Wolff M. Weitz M. Bartlau T. Korth C. Zerr I. Rapidly progressive Alzheimer disease.Arch. Neurol. 2011; 68: 1124-1130Crossref PubMed Scopus (115) Google Scholar). Neuropathological evaluation according to the NIA-AA guidelines (5Schellenberg G.D. Montine T.J. The genetics and neuropathology of Alzheimer's disease.Acta Neuropathol. 2012; 124: 305-323Crossref PubMed Scopus (169) Google Scholar, 17Cohen M.L. Kim C. Haldiman T. ElHag M. Mehndiratta P. Pichet T. Lissemore F. Shea M. Cohen Y. Chen W. Blevins J. Appleby B.S. Surewicz K. Surewicz W.K. Sajatovic M. et al.Rapidly progressive Alzheimer's disease features distinct structures of amyloid-β.Brain. 2015; 138: 1009-1022Crossref PubMed Scopus (117) Google Scholar) indicated a higher variance and trend toward more cases with less severe Aβ deposition in the rpAD group; the differences in other criteria including the pathology of tau using AT8 immunohistochemistry were not statistically significant (Fig. 1C and Table 1). In addition, diffuse Aβ and intracellular Aβ deposits in microglia and astrocytes (40Akiyama H. Mori H. Saido T. Kondo H. Ikeda K. McGeer P.L. Occurrence of the diffuse amyloid beta-protein (Abeta) deposits with numerous Abeta-containing glial cells in the cerebral cortex of patients with Alzheimer's disease.Glia. 1999; 25: 324-331Crossref PubMed Scopus (96) Google Scholar) occurred inconsistently in both rpAD and spAD cases, and if present, constituted a minor fraction of the total Aβ deposition (17Cohen M.L. Kim C. Haldiman T. ElHag M. Mehndiratta P. Pichet T. Lissemore F. Shea M. Cohen Y. Chen W. Blevins J. Appleby B.S. Surewicz K. Surewicz W.K. Sajatovic M. et al.Rapidly progressive Alzheimer's disease features distinct structures of amyloid-β.Brain. 2015; 138: 1009-1022Crossref PubMed Scopus (117) Google Scholar). Finally, as reported earlier by us and others (17Cohen M.L. Kim C. Haldiman T. ElHag M. Mehndiratta P. Pichet T. Lissemore F. Shea M. Cohen Y. Chen W. Blevins J. Appleby B.S. Surewicz K. Surewicz W.K. Sajatovic M. et al.Rapidly progressive Alzheimer's disease features distinct structures of amyloid-β.Brain. 2015; 138: 1009-1022Crossref PubMed Scopus (117) Google Scholar, 22Qiang W. Yau W.M. Lu J.X. Collinge J. Tycko R. Structural variation in amyloid-β fibrils from Alzheimer's disease clinical subtypes.Nature. 2017; 541: 217-221Crossref PubMed Scopus (329) Google Scholar), the amyloid plaque morphotypes and the deposits of hyperphosphorylated tau in all three cortex areas did not differ significantly between rpAD and spAD cases, and there were no pattern differences between rpAD cases with variable disease duration (Fig. 1C and Table 1). The NYU cohort of spAD showed significantly higher frequency of e4 APOE (apolipoprotein E gene with ε2, ε3, or ε4 allelic polymorphisms) alleles as previously with Case Western Reserve University cases (17Cohen M.L. Kim C. Haldiman T. ElHag M. Mehndiratta P. Pichet T. Lissemore F. Shea M. Cohen Y. Chen W. Blevins J. Appleby B.S. Surewicz K. Surewicz W.K. Sajatovic M. et al.Rapidly progressive Alzheimer's disease features distinct structures of amyloid-β.Brain. 2015; 138: 1009-1022Crossref PubMed Scopus (117) Google Scholar) (Fig. 1D and Table 1). Cumulatively, the consistent rapid progression rate and neuropathological findings of rpAD in prion and Alzheimer's centers across various methodologies, populations, and health care systems is evidence for a distinct and especially malignant form of sAD (11Cohen M. Appleby B. Safar J.G. Distinct prion-like strains of amyloid beta implicated in phenotypic diversity of Alzheimer's disease.Prion. 2016; 10: 9-17Crossref PubMed Scopus (43) Google Scholar, 17Cohen M.L. Kim C. Haldiman T. ElHag M. Mehndiratta P. Pichet T. Lissemore F. Shea M. Cohen Y. Chen W. Blevins J. Appleby B.S. Surewicz K. Surewicz W.K. Sajatovic M. et al.Rapidly progressive Alzheimer's disease features distinct structures of amyloid-β.Brain. 2015; 138: 1009-1022Crossref PubMed Scopus (117) Google Scholar, 37Pillai J.A. Appleby B.S. Safar J. Leverenz J.B. Rapidly progressive Alzheimer's disease in two distinct autopsy cohorts.J. Alzheimers Dis. 2018; 64: 973-980Crossref PubMed Scopus (10) Google Scholar, 39Schmidt C. Wolff M. Weitz M. Bartlau T. Korth C. Zerr I. Rapidly progressive Alzheimer disease.Arch. Neurol. 2011; 68: 1124-1130Crossref PubMed Scopus (115) Google Scholar, 41Schmidt C. Karch A. Artjomova S. Hoeschel M. Zerr I. Pre-progression rates in Alzheimer's disease revisited.J. Alzheimers Dis. 2013; 35: 451-454Crossref PubMed Scopus (5) Google Scholar, 42Schmidt C. Redyk K. Meissner B. Krack L. von Ahsen N. Roeber S. Kretzschmar H. Zerr I. Clinical features of rapidly progressive Alzheimer's disease.Dement Geriatr. Cogn. Disord. 2010; 29: 371-378Crossref PubMed Scopus (60) Google Scholar, 43Schmidt C. Wolff M. von Ahsen N. Zerr I. Alzheimer's disease: Genetic polymorphisms and rate of decline.Dement Geriatr. Cogn. Disord. 2012; 33: 84-89Crossref PubMed Scopus (27) Google Scholar).Table 1Demographics, clinicopathological characteristics, levels, and conformation of Aβ42 in the neocortex of AD cases with malignant rapidly progressive and classical slowly progressive disease phenotypeParameterUnitrpADSignificancespADnMinimumMaximumMean ± SEMpnMinimumMaximumMean ± SEMSexFemale/male15/17NS19/15AgeYears32548767.2 ± 1.6<0.001346110179.6 ± 1.8Disease durationFrom neurological follow-upMonth300.83914.3 ± 2.1<0.0013136300110.6 ± 10.0PMIh32212041.6 ± 5.43144215.8 ± 1.6ApoEe2n (%)1 (2.1)3 (4.4)e3n (%)33 (68.8)0.00335 (51.5)e4n (%)14 (29.2)30 (44.1)Neuropathological classificationARange30132.17 ± 0.180.00333132.79 ± 0.08BRange30132.57 ± 0.15NS33132.88 ± 0.07CRange30132.07 ± 0.20NS33132.36 ± 0.14Aβ42Frontalng/ml9304.1503.9384.9 ± 23.4NS11118.5619.3324.3 ± 36.7D/N ratio914.137.820.4 ± 2.4NS118.230.116.0 ± 2.2Occipitalng/ml96.3524.4282.6 ± 55.2NS1116.1667.8321.6 ± 54.8D/N ratio90.933.515.3 ± 2.9NS111.527.516.2 ± 2.7Temporalng/ml910.3507.5284.7 ± 55.3NS18223.7498.2332.5 ± 19.8D/N ratio90.928.518.1 ± 2.80.022189.933.324.4 ± 1.3Abbreviation: NS, not significant. Open table in a new tab Abbreviation: NS, not significant. To investigate levels and conformational characteristics of Aβ, we adopted an AlphaLISA-formatted CDI (12Haldiman T. Kim C. Cohen Y. Chen W. Blevins J. Qing L. Cohen M.L. Langeveld J. Telling G.C. Kong Q. Safar J.G. Co-existence of distinct prion types enables conformational evolution of human PrPSc by competitive selection.J. Biol. Chem. 2013; 288: 29846-29861Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar, 18Kim C. Haldiman T. Cohen Y. Chen W. Blevins J. Sy M.S. Cohen M. Safar J.G. Protease-sensitive conformers in broad spectrum of distinct PrPSc structures in sporadic Creutzfeldt-Jakob disease are indicator of progression rate.PLoS Pathog. 2011; 7e1002242Crossref PubMed Scopus (62) Google Scholar, 19Kim C. Haldiman T. Surewicz K. Cohen Y. Chen W. Blevins J. Sy M.S. Cohen M. Kong Q. Telling G.C. Surewicz W.K. Safar J.G. Small protease sensitive oligomers of PrPSc in distinct human prions determine conversion rate of PrP(C).PLoS Pathog. 2012; 8e1002835Crossref PubMed Scopus (62) Google Scholar, 21Safar J. Wille H. Itri V. Groth D. Serban H. Torchia M. Cohen F.E. Prusiner S.B. Eight prion strains have PrP(Sc) molecules with different conformations.Nat. Med. 1998; 4: 1157-1165Crossref PubMed Scopus (1045) Google Scholar). This extremely sensitive assay played a critical role in discovering that a variable proportion of pathogenic prion protein is composed of small protease-sensitive oligomers and also helped to establish that the conformation of pathogenic prion protein varies between distinct strains of prions (12Haldiman T. Kim C. Cohen Y. Chen W. Blevins J. Qing L. Cohen M.L. Langeveld J. Telling G.C. Kong Q. Safar J.G. Co-existence of distinct prion types enables conformational evolution of human PrPSc by competitive selection.J. Biol. Chem. 2013; 288: 29846-29861Abstract Full Text Full Text PDF PubMed Scopus (37) Google Scholar, 18Kim C. Haldiman T. Cohen Y. Chen W. Blevins J. Sy M.S. Cohen M. Safar J.G. Protease-sensitive conformers in broad spectrum of distinct PrPSc structures in sporadic Creutzfeldt-Jakob disease are indicator of progression rate.PLoS Pathog. 2011; 7e1002242Crossref PubMed Scopus (62) Google Scholar, 19Kim C. Haldiman T. Surewicz K. Cohen Y. Chen W. Blevins J. Sy M.S. Cohen M. Kong Q. Telling G.C. Surewicz W.K. Safar J.G. Small protease sensitive oligomers of PrPSc in distinct human prions determine conversion rate of PrP(C).PLoS Pathog. 2012; 8e1002835Crossref PubMed Scopus (62) Google Scholar, 21Safar J. Wille H. Itri V. Groth D. Serban H. Torchia M. Cohen F.E. Prusiner S.B. Eight prion strains have PrP(Sc) molecules with different conformations.Nat. Med. 1998; 4: 1157-1165Crossref PubMed Scopus (1045) Google Scholar). In principle, we adopted the AlphaLISA design with one antibody specific to the N terminus (monoclonal antibody [mAb] 4G8; epitope Aβ17-2
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