Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Position: (GRCh38/hg38):Chr14:73219188 C>T
Position: (GRCh37/hg19):Chr14:73685896 C>T
dbSNP ID: rs63750001
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: CTT to TTT
Reference Isoform: PSEN1 Isoform 1 (467 aa)
Genomic Region: Exon 12
Research Models: 1

Findings

This mutation was first reported in one out of 414 people with suspected Alzheimer's disease. However, no clinical, neuropathological, or family details were reported (Rogaeva et al., 2001).

The L435F mutation was subsequently identified in two siblings with a family history of early onset AD (Heilig et al., 2010). The reported pedigree shows a third affected sibling, as well as their affected father. The average age of onset was 47 years, and the average age at death was 56 years. Disease in this family presented as early and progressive memory problems and aphasia. Motor symptoms, including parkinsonism, developed later, but not spastic paraparesis. The mutation was found in both of the affected siblings tested.

This variant was absent from the gnomAD variant database (gnomAD v2.1.1, August 2021).

Neuropathology

Neuropathological analysis of the two affected mutation carriers showed numerous and widespread cotton-wool plaques throughout the neocortex, hippocampus, and deep cerebral nuclei. These large plaques lacked a dense core and were associated with neuritic dystrophy. Some neurofibrillary tangles were observed in the cortex, with high concentrations in the entorhinal cortex and hippocampus. Evidence of mild cerebral amyloid angiopathy was present in vessels. The substantia nigra was affected by neuronal loss, depigmentation, and gliosis (Heilig et al., 2010). The plaques in the frontal cortex and hippocampus contained Aβ40 and Aβ42, but also substantially more Aβ43 relative to plaques in AD patients without the L435F mutation (Kretner et al., 2016). Strong Aβ43 staining was also reported in the brain of another L435F mutation carrier (Oakley et al., 2020).

Biological Effect

Observations in patient brains, cell lines, rodent models, and in vitro experiments have shown this mutation disrupts the proteolytic processing of APP and Notch-1. Of particular interest, L435F has been reported to increase levels of Aβ43, an aggregating and neurotoxic peptide proposed to play an important role in the onset of pathological amyloid deposition (Kretner et al., 2016; Veugelen et al., 2016; April 2016 news; Trambauer et al., 2020; Tambini and D'Adamio, 2020, Oakley et al., 2020; Tambini et al., 2023). Early studies, however, focused on other consequences of this substitution: its reduction of total amyloid production, including lower levels of Aβ40, Aβ42, and the APP C-terminal fragment (Heilig et al., 2010; Sun et al., 2017). These findings were considered supportive of the hypothesis that loss of presenilin function plays an important role in at least some cases of familial AD pathogenesis. Indeed, in a heterozygous L435F knockin mouse, Xia and colleagues found decreased levels of Aβ40 and Aβ42 (Xia et al., 2015; Mar 2015 news).

Subsequent studies in cells (Kretner et al., 2016; Veugelen et al., 2016; April 2016 news), including neurons derived from induced pluripotent stem cells (iPSCs) from a mutation carrier (Oakley et al., 2020), and in human brain tissue (Kretner et al., 2016; Oakley et al., 2020), however, revealed the mutation increases levels of Aβ43. In addition, although decreased levels of Aβ43 were reported in heterozygous knockin mice (Xia et al., 2016), the peptide was found to be elevated in both heterozygous and homozygous knockin rats (Tambini and D'Adamio, 2020; Tambini et al., 2023). Of note, in the iPSC-derived neurons, soluble Aβ40 and Aβ42 were similar to controls (Oakley et al., 2020). 

Assays using purified PSEN1 complexes and a tagged APPC99 substrate revealed PSEN1 L435F is more sensitive to increased temperatures than wildtype PSEN1, suggesting the mutation destabilizes the interaction required for proteolysis of APPC99 and newly produced Aβn substrates, resulting in the release of longer Aβ peptides (Szaruga et al., 2017). This effect is particularly evident for the Aβ49 product line, resulting in substantial decreases in Aβ46→Aβ43 (Devkota et al., 2024) and Aβ43→Aβ40 (Tambini et al., 2023) trimming.

The mutation also seems to affect PSEN1 function by drastically reducing ε-cleavage (Do et al., 2023; Devkota et al., 2024) and nearly abrogating autoproteolysis (Sun et al., 2017; Trambauer et al., 2020). Moreover, a dominant-negative effect on wild-type PSEN1 may also contribute to its pathogenecity. Experiments using cultured cells and isolated proteins revealed the mutant alters production of Aβ peptides by wild-type presenilin, an effect that was differentially sensitive to detergents suggesting inhibition through hetero-oligomerization (Heilig et al., 2013; Zhou et al., 2017). 

L435 has been shown to directly interact with APP, forming part of the PAL motif implicated in the recognition of APP by γ-secretase (Sato et al., 2008; Zhou et al., 2019; Jan 2019 news). Consistent with these findings, cross-linking experiments revealed disrupted interactions between the mutant and the Aβ peptide precursor C99 (Trambauer et al., 2020). Moreover, computational simulations suggested the substitution of leucine by phenylalanine at this position results in the loss of hydrogen bonding between the PAL motif and the substrate which affects the positioning of the cleavage region (Dehury et al., 2020). It has also been suggested that the substitution could create steric clashes within the PSEN1 active site, increasing the distance between the two catalytic aspartates D257 and D385 (Do et al., 2023).  These authors noted their proposal is consistent with other computational simulations (Chen and Zacharias, 2020), and predicted the active subpocket of the mutant protein is smaller than that of wildtype PSEN1, with the APP-bound active site being more restricted (Do et al., 2023).

L435F, as well as other familial AD mutations, appear to stall the γ-secretase-substrate complex and the presence of this membrane-anchored complex per se is toxic (Devkota et al., 2024; Nov 2023 news). Moreover, a dominant-negative effect on wild-type PSEN1 may also contribute to L435F’s pathogenicity. Experiments using cultured cells and isolated proteins revealed the mutant alters production of Aβ peptides by wild-type presenilin, an effect that was differentially sensitive to detergents suggesting inhibition through hetero-oligomerization (Heilig et al., 2013; Zhou et al., 2017).

L435F may also have AD-relevant effects beyond the alteration of APP processing. One possibility is that the variant’s effects on Notch1 processing contribute to AD pathology, although L435F’s effects on Notch signaling remain controversial. Homozygous L435F mice are perinatally lethal and have similar phenotypes to those of PSEN1 null mutants, presumably because of disruption of Notch signaling (Xia et al., 2015). Indeed, studies in these mice, as well as in mutant rats (Tambini and D’Adamio, 2020), indicated reduced levels of the Notch intracellular domain. However, a study using heterozygote human cortical spheroids generated from induced pluripotent stem cells, found little or no effect on NICD levels, and instead revealed increased Notch target gene expression during early spheroid development (Hurley et al., 2023). The mutant-derived spheroids were larger, had more progenitor cells, and less postmitotic neurons, suggesting L435F increased Notch1 processing during neurodevelopment, increasing Notch signaling and reducing neuronal differentiation. Also of note, experiments in IPSC-derived neurons from a mutation carrier suggest L435 may accelerate seeding of tau aggregates and influence tau propagation (Oakley et al., 2021).

Several in silico algorithms (SIFT, Polyphen-2, LRT, MutationTaster, MutationAssessor, FATHMM, PROVEAN, CADD, REVEL, and Reve in the VarCards database) predicted this variant is damaging (Xiao et al., 2021).

Pathogenicity

Alzheimer's Disease : Pathogenic

This variant fulfilled the following criteria based on the ACMG/AMP guidelines. See a full list of the criteria in the Methods page.

Research Models

Heterozygous knockin mice carrying human presenilin-1 with the L435F mutation develop deficits in synaptic plasticity and memory as well as age-related neurodegeneration. The mutant presenilin-1 led to perinatal lethality in homozygous mice (Xia et al., 2015). In rats, however, knockin homozygosity is not lethal and the animals survive to adulthood, expressing low levels of Aβ38, Aβ40, and Aβ42, but high levels of Aβ43 (Tambini and D'Adamio, 2020, PSEN1 L435F knock-in). Also, induced pluripotent stem cell (iPSC) lines have been generated from mutation carrier cells and differentiated into neurons (Oakley et al., 2020). When compared to iPSC-derived neurons from  non-carriers, these cells produced similar levels of soluble Aβ40 and Aβ42, but high levels of Aβ43. In addition, they underwent tau seeding more rapidly (Oakley et al., 2021). 

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References

Research Models Citations

1. Psen1 L435F knock-in

News Citations

1. Pathogenic Presenilin Mutations Generate Aβ43 29 Apr 2016
2. Mutant Presenilin Knock-in Mice Mimic Knockouts, Stir Old Debate 10 Mar 2015
3. CryoEM γ-Secretase Structures Nail APP, Notch Binding 11 Jan 2019
4. Patricidal Protein? Aβ42 said to Inhibit Its Parent, γ-Secretase 17 Nov 2023

Paper Citations

1. Xia D, Watanabe H, Wu B, Lee SH, Li Y, Tsvetkov E, Bolshakov VY, Shen J, Kelleher RJ 3rd. Presenilin-1 knockin mice reveal loss-of-function mechanism for familial Alzheimer's disease. Neuron. 2015 Mar 4;85(5):967-81. PubMed.
2. Tambini MD, D'Adamio L. Knock-in rats with homozygous PSEN1L435F Alzheimer mutation are viable and show selective γ-secretase activity loss causing low Aβ40/42 and high Aβ43. J Biol Chem. 2020 May 22;295(21):7442-7451. Epub 2020 Apr 7 PubMed.
3. Oakley DH, Chung M, Klickstein N, Commins C, Hyman BT, Frosch MP. The Alzheimer Disease-Causing Presenilin-1 L435F Mutation Causes Increased Production of Soluble Aβ43 Species in Patient-Derived iPSC-Neurons, Closely Mimicking Matched Patient Brain Tissue. J Neuropathol Exp Neurol. 2020 Jun 1;79(6):592-604. PubMed.
4. Oakley DH, Klickstein N, Commins C, Chung M, Dujardin S, Bennett RE, Hyman BT, Frosch MP. Continuous Monitoring of Tau-Induced Neurotoxicity in Patient-Derived iPSC-Neurons. J Neurosci. 2021 May 12;41(19):4335-4348. Epub 2021 Apr 23 PubMed.
5. Rogaeva EA, Fafel KC, Song YQ, Medeiros H, Sato C, Liang Y, Richard E, Rogaev EI, Frommelt P, Sadovnick AD, Meschino W, Rockwood K, Boss MA, Mayeux R, St George-Hyslop P. Screening for PS1 mutations in a referral-based series of AD cases: 21 novel mutations. Neurology. 2001 Aug 28;57(4):621-5. PubMed.
6. Heilig EA, Xia W, Shen J, Kelleher RJ. A presenilin-1 mutation identified in familial Alzheimer disease with cotton wool plaques causes a nearly complete loss of gamma-secretase activity. J Biol Chem. 2010 Jul 16;285(29):22350-9. PubMed.
7. 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 Aβ43 by the virtually inactive presenilin-1 L435F mutant contradicts the presenilin loss-of-function hypothesis of Alzheimer's disease. EMBO Mol Med. 2016 May 2;8(5):458-65. PubMed.
8. Veugelen S, Saito T, Saido TC, Chávez-Gutiérrez L, De Strooper B. Familial Alzheimer's Disease Mutations in Presenilin Generate Amyloidogenic Aβ Peptide Seeds. Neuron. 2016 Apr 20;90(2):410-6. PubMed.
9. Trambauer J, Rodríguez Sarmiento RM, Fukumori A, Feederle R, Baumann K, Steiner H. Aβ43-producing PS1 FAD mutants cause altered substrate interactions and respond to γ-secretase modulation. EMBO Rep. 2020 Jan 7;21(1):e47996. Epub 2019 Nov 25 PubMed.
10. Tambini MD, Yin T, Yesiltepe M, Breuillaud L, Zehntner SP, d'Abramo C, Giliberto L, D'Adamio L. Aβ43 levels determine the onset of pathological amyloid deposition. J Biol Chem. 2023 Jul;299(7):104868. Epub 2023 May 29 PubMed.
11. Sun L, Zhou R, Yang G, Shi Y. Analysis of 138 pathogenic mutations in presenilin-1 on the in vitro production of Aβ42 and Aβ40 peptides by γ-secretase. Proc Natl Acad Sci U S A. 2017 Jan 24;114(4):E476-E485. Epub 2016 Dec 5 PubMed.
12. Xia D, Kelleher RJ 3rd, Shen J. Loss of Aβ43 Production Caused by Presenilin-1 Mutations in the Knockin Mouse Brain. Neuron. 2016 Apr 20;90(2):417-22. PubMed.
13. Szaruga M, Munteanu B, Lismont S, Veugelen S, Horré K, Mercken M, Saido TC, Ryan NS, De Vos T, Savvides SN, Gallardo R, Schymkowitz J, Rousseau F, Fox NC, Hopf C, De Strooper B, Chávez-Gutiérrez L. Alzheimer's-Causing Mutations Shift Aβ Length by Destabilizing γ-Secretase-Aβn Interactions. Cell. 2017 Jul 27;170(3):443-456.e14. PubMed. Correction.
14. Devkota S, Zhou R, Nagarajan V, Maesako M, Do H, Noorani A, Overmeyer C, Bhattarai S, Douglas JT, Saraf A, Miao Y, Ackley BD, Shi Y, Wolfe MS. Familial Alzheimer mutations stabilize synaptotoxic γ-secretase-substrate complexes. Cell Rep. 2024 Feb 27;43(2):113761. Epub 2024 Feb 13 PubMed.
15. Do HN, Devkota S, Bhattarai A, Wolfe MS, Miao Y. Effects of presenilin-1 familial Alzheimer's disease mutations on γ-secretase activation for cleavage of amyloid precursor protein. Commun Biol. 2023 Feb 14;6(1):174. PubMed.
16. Heilig EA, Gutti U, Tai T, Shen J, Kelleher RJ. Trans-dominant negative effects of pathogenic PSEN1 mutations on γ-secretase activity and Aβ production. J Neurosci. 2013 Jul 10;33(28):11606-17. PubMed.
17. Zhou R, Yang G, Shi Y. Dominant negative effect of the loss-of-function γ-secretase mutants on the wild-type enzyme through heterooligomerization. Proc Natl Acad Sci U S A. 2017 Nov 28;114(48):12731-12736. Epub 2017 Oct 9 PubMed.
18. Sato C, Takagi S, Tomita T, Iwatsubo T. The C-terminal PAL motif and transmembrane domain 9 of presenilin 1 are involved in the formation of the catalytic pore of the gamma-secretase. J Neurosci. 2008 Jun 11;28(24):6264-71. PubMed.
19. Zhou R, Yang G, Guo X, Zhou Q, Lei J, Shi Y. Recognition of the amyloid precursor protein by human γ-secretase. Science. 2019 Feb 15;363(6428) Epub 2019 Jan 10 PubMed.
20. Dehury B, Somavarapu AK, Kepp KP. A computer-simulated mechanism of familial Alzheimer's disease: Mutations enhance thermal dynamics and favor looser substrate-binding to γ-secretase. J Struct Biol. 2020 Dec 1;212(3):107648. Epub 2020 Oct 21 PubMed.
21. Chen SY, Zacharias M. How Mutations Perturb γ-Secretase Active Site Studied by Free Energy Simulations. ACS Chem Neurosci. 2020 Oct 21;11(20):3321-3332. Epub 2020 Oct 6 PubMed.
22. Hurley EM, Mozolewski P, Dobrowolski R, Hsieh J. Familial Alzheimer's disease-associated PSEN1 mutations affect neurodevelopment through increased Notch signaling. Stem Cell Reports. 2023 Jul 11;18(7):1516-1533. Epub 2023 Jun 22 PubMed.
23. Xiao X, Liu H, Liu X, Zhang W, Zhang S, Jiao B. APP, PSEN1, and PSEN2 Variants in Alzheimer's Disease: Systematic Re-evaluation According to ACMG Guidelines. Front Aging Neurosci. 2021;13:695808. Epub 2021 Jun 18 PubMed.

External Citations

1. gnomAD v2.1.1

Further Reading