Spectrum of γ-Secretase dysfunction as a unifying predictor of ADAD age at onset across PSEN1, PSEN2 and APP causal genes

Scheltens P, De Strooper B, Kivipelto M, Holstege H, Chetelat G, Teunissen CE, Cummings J, van der Flier WM. Alzheimer’s disease. Lancet. 2021;397:1577–90.

Article  PubMed  PubMed Central  CAS  Google Scholar 

Chavez-Gutierrez L, Szaruga M. Mechanisms of neurodegeneration - Insights from familial Alzheimer’s disease. Semin Cell Dev Biol. 2020;105:75–85.

Article  PubMed  CAS  Google Scholar 

Ryman DC, Acosta-Baena N, Aisen PS, Bird T, Danek A, Fox NC, Goate A, Frommelt P, Ghetti B, Langbaum JB, et al. Symptom onset in autosomal dominant Alzheimer disease: a systematic review and meta-analysis. Neurology. 2014;83:253–60.

Article  PubMed  PubMed Central  CAS  Google Scholar 

Bateman RJ, Aisen PS, De Strooper B, Fox NC, Lemere CA, Ringman JM, Salloway S, Sperling RA, Windisch M, Xiong C. Autosomal-dominant Alzheimer’s disease: a review and proposal for the prevention of Alzheimer’s disease. Alzheimers Res Ther. 2011;3:1.

Article  PubMed  PubMed Central  Google Scholar 

Acx H, Chavez-Gutierrez L, Serneels L, Lismont S, Benurwar M, Elad N, De Strooper B. Signature amyloid beta profiles are produced by different gamma-secretase complexes. J Biol Chem. 2014;289:4346–55.

Article  PubMed  CAS  Google Scholar 

Sannerud R, Esselens C, Ejsmont P, Mattera R, Rochin L, Tharkeshwar AK, De Baets G, De Wever V, Habets R, Baert V, et al. Restricted Location of PSEN2/gamma-Secretase Determines Substrate Specificity and Generates an Intracellular Abeta Pool. Cell. 2016;166:193–208.

Article  PubMed  PubMed Central  CAS  Google Scholar 

Takami M, Nagashima Y, Sano Y, Ishihara S, Morishima-Kawashima M, Funamoto S, Ihara Y. gamma-Secretase: successive tripeptide and tetrapeptide release from the transmembrane domain of beta-carboxyl terminal fragment. J Neurosci. 2009;29:13042–52.

Article  PubMed  PubMed Central  CAS  Google Scholar 

Vassar R, Bennett BD, Babu-Khan S, Kahn S, Mendiaz EA, Denis P, Teplow DB, Ross S, Amarante P, Loeloff R, et al. Beta-secretase cleavage of Alzheimer’s amyloid precursor protein by the transmembrane aspartic protease BACE. Science. 1999;286:735–41.

Article  PubMed  CAS  Google Scholar 

Chavez-Gutierrez L, Bammens L, Benilova I, Vandersteen A, Benurwar M, Borgers M, Lismont S, Zhou L, Van Cleynenbreugel S, Esselmann H, et al. The mechanism of gamma-Secretase dysfunction in familial Alzheimer disease. EMBO J. 2012;31:2261–74.

Article  PubMed  PubMed Central  CAS  Google Scholar 

Szaruga M, Veugelen S, Benurwar M, Lismont S, Sepulveda-Falla D, Lleo A, Ryan NS, Lashley T, Fox NC, Murayama S, et al. Qualitative changes in human gamma-secretase underlie familial Alzheimer’s disease. J Exp Med. 2015;212:2003–13.

Article  PubMed  PubMed Central  CAS  Google Scholar 

Szaruga M, Munteanu B, Lismont S, Veugelen S, Horre K, Mercken M, Saido TC, Ryan NS, De Vos T, Savvides SN, et al. Alzheimer’s-Causing Mutations Shift Abeta Length by Destabilizing gamma-Secretase-Abetan Interactions. Cell. 2017;170(443–456): e414.

Google Scholar 

Duff K, Eckman C, Zehr C, Yu X, Prada CM, Perez-tur J, Hutton M, Buee L, Harigaya Y, Yager D, et al. Increased amyloid-beta42(43) in brains of mice expressing mutant presenilin 1. Nature. 1996;383:710–3.

Article  PubMed  CAS  Google Scholar 

Borchelt DR, Thinakaran G, Eckman CB, Lee MK, Davenport F, Ratovitsky T, Prada CM, Kim G, Seekins S, Yager D, et al. Familial Alzheimer’s disease-linked presenilin 1 variants elevate Abeta1-42/1-40 ratio in vitro and in vivo. Neuron. 1996;17:1005–13.

Article  PubMed  CAS  Google Scholar 

Scheuner D, Eckman C, Jensen M, Song X, Citron M, Suzuki N, Bird TD, Hardy J, Hutton M, Kukull W, et al. Secreted amyloid beta-protein similar to that in the senile plaques of Alzheimer’s disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer’s disease. Nat Med. 1996;2:864–70.

Article  PubMed  CAS  Google Scholar 

Citron M, Westaway D, Xia W, Carlson G, Diehl T, Levesque G, Johnson-Wood K, Lee M, Seubert P, Davis A, et al. Mutant presenilins of Alzheimer’s disease increase production of 42-residue amyloid beta-protein in both transfected cells and transgenic mice. Nat Med. 1997;3:67–72.

Article  PubMed  CAS  Google Scholar 

Murayama O, Tomita T, Nihonmatsu N, Murayama M, Sun X, Honda T, Iwatsubo T, Takashima A. Enhancement of amyloid beta 42 secretion by 28 different presenilin 1 mutations of familial Alzheimer’s disease. Neurosci Lett. 1999;265:61–3.

Article  PubMed  CAS  Google Scholar 

Veugelen S, Saito T, Saido TC, Chavez-Gutierrez L, De Strooper B. Familial Alzheimer’s Disease Mutations in Presenilin Generate Amyloidogenic Abeta Peptide Seeds. Neuron. 2016;90:410–6.

Article  PubMed  CAS  Google Scholar 

Saito T, Suemoto T, Brouwers N, Sleegers K, Funamoto S, Mihira N, Matsuba Y, Yamada K, Nilsson P, Takano J, et al. Potent amyloidogenicity and pathogenicity of Abeta43. Nat Neurosci. 2011;14:1023–32.

Article  PubMed  CAS  Google Scholar 

Kretner B, Trambauer J, Fukumori A, Mielke J, Kuhn PH, Kremmer E, Giese A, Lichtenthaler SF, Haass C, Arzberger T, Steiner H. Generation and deposition of Abeta43 by the virtually inactive presenilin-1 L435F mutant contradicts the presenilin loss-of-function hypothesis of Alzheimer’s disease. EMBO Mol Med. 2016;8:458–65.

Article  PubMed  PubMed Central  CAS  Google Scholar 

Seuma M, Lehner B, Bolognesi B. An atlas of amyloid aggregation: the impact of substitutions, insertions, deletions and truncations on amyloid beta fibril nucleation. Nat Commun. 2022;13:7084.

Article  PubMed  PubMed Central  CAS  Google Scholar 

Zhang Y, Chen H, Li R, Sterling K, Song W. Amyloid beta-based therapy for Alzheimer’s disease: challenges, successes and future. Signal Transduct Target Ther. 2023;8:248.

Article  PubMed  PubMed Central  CAS  Google Scholar 

Jucker M, Walker LC. Alzheimer’s disease: From immunotherapy to immunoprevention. Cell. 2023;186:4260–70.

Article  PubMed  PubMed Central  CAS  Google Scholar 

Petit D, Fernandez SG, Zoltowska KM, Enzlein T, Ryan NS, O’Connor A, Szaruga M, Hill E, Vandenberghe R, Fox NC, Chavez-Gutierrez L. Abeta profiles generated by Alzheimer’s disease causing PSEN1 variants determine the pathogenicity of the mutation and predict age at disease onset. Mol Psychiatry. 2022;27:2821–32.

Article  PubMed  PubMed Central  CAS  Google Scholar 

Schultz SA, Liu L, Schultz AP, Fitzpatrick CD, Levin R, Bellier JP, Shirzadi Z, Joseph-Mathurin N, Chen CD, Benzinger TLS, et al. gamma-Secretase activity, clinical features, and biomarkers of autosomal dominant Alzheimer’s disease: cross-sectional and longitudinal analysis of the Dominantly Inherited Alzheimer Network observational study (DIAN-OBS). Lancet Neurol. 2024;23:913–24.

Article  PubMed  CAS  Google Scholar 

Ryan NS, Nicholas JM, Weston PSJ, Liang Y, Lashley T, Guerreiro R, Adamson G, Kenny J, Beck J, Chavez-Gutierrez L, et al. Clinical phenotype and genetic associations in autosomal dominant familial Alzheimer’s disease: a case series. Lancet Neurol. 2016;15:1326–35.

Article  PubMed  Google Scholar 

Wang G, Zhang DF, Jiang HY, Fan Y, Ma L, Shen Z, Bi R, Xu M, Tan L, Shan B, et al. Mutation and association analyses of dementia-causal genes in Han Chinese patients with early-onset and familial Alzheimer’s disease. J Psychiatr Res. 2019;113:141–7.

Article  PubMed  Google Scholar 

Jia L, Fu Y, Shen L, Zhang H, Zhu M, Qiu Q, Wang Q, Yan X, Kong C, Hao J, et al. PSEN1, PSEN2, and APP mutations in 404 Chinese pedigrees with familial Alzheimer’s disease. Alzheimers Dement. 2020;16:178–91.

Article  PubMed  Google Scholar 

Mao C, Li J, Dong L, Huang X, Lei D, Wang J, Chu S, Liu C, Peng B, Roman GC, et al. Clinical Phenotype and Mutation Spectrum of Alzheimer’s Disease with Causative Genetic Mutation in a Chinese Cohort. Curr Alzheimer Res. 2021;18:265–72.

Article  PubMed 

Comments (0)

No login
gif