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Current Alzheimer Research

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ISSN (Print): 1567-2050
ISSN (Online): 1875-5828

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Research Article

Novel PSEN1 (P284S) Mutation Causes Alzheimer's Disease with Cerebellar Amyloid β-Protein Deposition

Author(s): Mingrong Xia, Chenhao Gao, Huayuan Wang, Junkui Shang, Ruijie Liu, Yang You, Weizhou Zang* and Jiewen Zhang*

Volume 19, Issue 7, 2022

Published on: 22 September, 2022

Page: [523 - 529] Pages: 7

DOI: 10.2174/1567205019666220718151357

open access plus

Abstract

Background/Objective: AD-associated PSEN1 mutations exhibit high clinical heterogeneity. The discovery of these mutations and the analysis of their associations with cases such as EOAD should be critical to understanding AD's pathogenesis.

Methods: We performed clinical analysis, neuroimaging, target region capture and high-throughput sequencing, and Sanger sequencing in a family of 3 generations. The underlying Alzheimer’s pathology was evaluated using biomarker evidence obtained from cerebrospinal fluid (CSF) amyloid testing and 18F-florbetapir (AV-45) PET imaging.

Results: Target region capture sequencing revealed a novel heterozygous C to T missense point mutation at the base position 284 (c.850 C>T) located in exon 8 of the PSEN1 gene, resulting in a Prolineto- Serine substitution (P284S) at codon position 850. The mutation was also identified by Sanger sequencing in 2 family members, including proband and her daughter and was absent in the other 4 unaffected family members and 50 control subjects. Cerebrospinal fluid (CSF) amyloid test exhibited biomarker evidence of underlying Alzheimer’s pathology. 18F-florbetapir (AV-45) PET imaging indicated extensive cerebral cortex and cerebellar Aβ deposition.

Conclusions: We discovered a novel PSEN1 pathogenic mutation, P284S, observed for the first time in a Chinese family with early-onset AD.

Keywords: Alzheimer's disease, PSEN1, P284S mutation, 18F-florbetapir (AV-45) PET, cerebellar Aβ deposition, cerebral cortex

« Previous Next »
[1]
Giau VV, Senanarong V, Bagyinszky E, An SSA, Kim S. Analysis of 50 neurodegenerative genes in clinically diagnosed early-onset Alzheimer’s Disease. Int J Mol Sci 2019; 20(6): 1514.
[http://dx.doi.org/10.3390/ijms20061514] [PMID: 30917570]
[2]
Guerreiro RJ, Baquero M, Blesa R, et al. Genetic screening of Alzheimer’s disease genes in Iberian and African samples yields novel mutations in presenilins and APP. Neurobiol Aging 2010; 31(5): 725-31.
[http://dx.doi.org/10.1016/j.neurobiolaging.2008.06.012] [PMID: 18667258]
[3]
Giau VV, Lee H, Shim KH, Bagyinszky E, An SSA. Genome-editing applications of CRISPR-Cas9 to promote in vitro studies of Alzheimer’s disease. Clin Interv Aging 2018; 13: 221-33.
[http://dx.doi.org/10.2147/CIA.S155145] [PMID: 29445268]
[4]
Van der Flier WM. Clinical heterogeneity in familial Alzheimer’s disease. Lancet Neurol 2016; 15(13): 1296-8.
[http://dx.doi.org/10.1016/S1474-4422(16)30275-7] [PMID: 27777021]
[5]
McKhann GM, Knopman DS, Chertkow H, et al. The diagnosis of dementia due to Alzheimer’s disease: Recommendations from the National Institute on Aging-Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s disease. Alzheimers Dement 2011; 7(3): 263-9.
[http://dx.doi.org/10.1016/j.jalz.2011.03.005] [PMID: 21514250]
[6]
Jagust WJ, Bandy D, Chen K, et al. The Alzheimer’s disease neuroimaging initiative positron emission tomography core. Alzheimers Dement 2010; 6(3): 221-9.
[http://dx.doi.org/10.1016/j.jalz.2010.03.003] [PMID: 20451870]
[7]
Marrosu MG, Floris G, Costa G, et al. Dementia, pyramidal system involvement, and leukoencephalopathy with a presenilin 1 mutation. Neurology 2006; 66(1): 108-11.
[http://dx.doi.org/10.1212/01.wnl.0000191360.08881.12] [PMID: 16401857]
[8]
Floris G, Di Stefano F, Cherchi MV, Costa G, Marrosu F, Marrosu MG. Multiple spontaneous cerebral microbleeds and leukoencephalopathy in PSEN1-associated familial Alzheimer’s disease: Mirror of cerebral amyloid angiopathy? J Alzheimers Dis 2015; 47(3): 535-8.
[http://dx.doi.org/10.3233/JAD-150165] [PMID: 26401689]
[9]
Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: A joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015; 17(5): 405-24.
[http://dx.doi.org/10.1038/gim.2015.30] [PMID: 25741868]
[10]
Jack CR Jr, Bennett DA, Blennow K, et al. NIA-AA research framework: Toward a biological definition of Alzheimer’s disease. Alzheimers Dement 2018; 14(4): 535-62.
[http://dx.doi.org/10.1016/j.jalz.2018.02.018] [PMID: 29653606]
[11]
Lim EW, Aarsland D, Ffytche D, et al. Amyloid-β and Parkinson’s disease. J Neurol 2019; 266(11): 2605-19.
[http://dx.doi.org/10.1007/s00415-018-9100-8] [PMID: 30377818]
[12]
Oh YS, Yoo SW, Lyoo CH, et al. The association of β-amyloid with cognition and striatal dopamine in early, non-demented Parkinson’s disease. J Parkinsons Dis 2021; 11(2): 605-13.
[http://dx.doi.org/10.3233/JPD-202496] [PMID: 33646180]
[13]
Yoo HS, Lee S, Chung SJ. Clinical and striatal dopamine transporter predictors of β-amyloid in dementia with Lewy bodies. 2020; 94: e1344-1352.
[14]
Aarsland D, Creese B, Politis M, et al. Cognitive decline in Parkinson’s disease. Nat Rev Neurol 2017; 13(4): 217-31.
[http://dx.doi.org/10.1038/nrneurol.2017.27] [PMID: 28257128]
[15]
Nakano K, Kayahara T, Tsutsumi T, Ushiro H. Neural circuits and functional organization of the striatum. J Neurol 2000; 247(S5) (Suppl. 5): V1-V15.
[http://dx.doi.org/10.1007/PL00007778] [PMID: 11081799]
[16]
Kalaitzakis ME, Graeber MB, Gentleman SM, Pearce RK. Striatal beta-amyloid deposition in Parkinson’s disease with dementia. J Neuropathol Exp Neurol 2008; 67(2): 155-61.
[http://dx.doi.org/10.1097/NEN.0b013e31816362aa] [PMID: 18219254]
[17]
Kalaitzakis ME, Walls AJ, Pearce RK, Gentleman SM. Striatal Aβ peptide deposition mirrors dementia and differentiates DLB and PDD from other parkinsonian syndromes. Neurobiol Dis 2011; 41(2): 377-84.
[http://dx.doi.org/10.1016/j.nbd.2010.10.005] [PMID: 20951207]
[18]
Halliday GM, Song YJ, Harding AJ. Striatal β-amyloid in dementia with Lewy bodies but not Parkinson’s disease. J Neural Transm (Vienna) 2011; 118(5): 713-9.
[http://dx.doi.org/10.1007/s00702-011-0641-6] [PMID: 21479514]
[19]
Alafuzoff I, Thal DR, Arzberger T, et al. Assessment of beta-amyloid deposits in human brain: A study of the BrainNet Europe Consortium. Acta Neuropathol 2009; 117(3): 309-20.
[http://dx.doi.org/10.1007/s00401-009-0485-4] [PMID: 19184666]
[20]
Thal DR, Rüb U, Orantes M, Braak H. Phases of A beta-deposition in the human brain and its relevance for the development of AD. Neurology 2002; 58(12): 1791-800.
[http://dx.doi.org/10.1212/WNL.58.12.1791] [PMID: 12084879]
[21]
Klunk WE, Price JC, Mathis CA, et al. Amyloid deposition begins in the striatum of presenilin-1 mutation carriers from two unrelated pedigrees. J Neurosci 2007; 27(23): 6174-84.
[http://dx.doi.org/10.1523/JNEUROSCI.0730-07.2007] [PMID: 17553989]
[22]
Koivunen J, Verkkoniemi A, Aalto S, et al. PET amyloid ligand [11C]PIB uptake shows predominantly striatal increase in variant Alzheimer’s disease. Brain 2008; 131(Pt 7): 1845-53.
[http://dx.doi.org/10.1093/brain/awn107] [PMID: 18583368]
[23]
Lemere CA, Lopera F, Kosik KS, et al. The E280A presenilin 1 Alzheimer mutation produces increased A beta 42 deposition and severe cerebellar pathology. Nat Med 1996; 2(10): 1146-50.
[http://dx.doi.org/10.1038/nm1096-1146] [PMID: 8837617]
[24]
Verdile G, Gnjec A, Miklossy J, et al. Protein markers for Alzheimer’s disease in the frontal cortex and cerebellum. Neurology 2004; 63(8): 1385-92.
[http://dx.doi.org/10.1212/01.WNL.0000141848.45315.A6] [PMID: 15505153]

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