Overview

Pathogenicity: Alzheimer's Disease : Pathogenic
ACMG/AMP Pathogenicity Criteria: PS3, PM1, PM2, PP2, PP3
Clinical Phenotype: Alzheimer's Disease
Reference Assembly: GRCh37/hg19
Position: Chr21:27264099 A>T
dbSNP ID: NA
Coding/Non-Coding: Coding
DNA Change: Substitution
Expected RNA Consequence: Substitution
Expected Protein Consequence: Missense
Codon Change: ATC to TTC
Reference Isoform: APP Isoform APP770 (770 aa)
Genomic Region: Exon 17
Research Models: 5

Findings

This mutation was first detected in a Caucasian patient of Spanish or Portuguese ancestry who was diagnosed with probable Alzheimer's disease according to DSM-IV and NINCDS-ADRDA criteria. Clinical symptoms began at age 31 and the patient died two years later. The patient had a family history of AD, although it was not possible to evaluate segregation of the mutation with disease (Guerreiro et al., 2010).

This mutation was later reported in two members of a Kurdish family affected by a familial dementia syndrome described as reminiscent of Creutzfeldt-Jakob disease because it involved prominent cerebellar ataxia and other motor features in addition to rapid cognitive decline (Sieczkowski et al., 2015). The reported pedigree shows five affected family members over four generations. The proband developed symptoms at age 47, starting with gait disturbance and uncoordinated jerky movements of the right arm. He had a three-year history of severe depression. Within one year of developing motor symptoms, he developed rapid cognitive decline and dementia. He developed seizures and was bedridden at age 49. He died at age 55. His brother had died at age 37 with a diagnosis of CJD following a similar disease course. No autopsy was performed. The proband’s mother had died in her 30s with dementia, but further clinical details were not available. The proband’s niece, who also carried the mutation, showed signs of cognitive decline at the time of the report. 

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

Neuropathology

The I716F mutation is associated with extensive and often mixed neuropathology, characterized by typical AD pathology (e.g., amyloid plaques and neurofibrillary tangles), in addition to α-synuclein pathology in some cases. For example, in one case, primarily AD pathology was observed, namely neurofibrillary changes (Braak stage VI) and amyloid deposits (CERAD stage C) (Guerreiro et al., 2010). In another case, Lewy bodies were observed in the amygdala along with abundant diffuse amyloid plaques, composed mainly of Aβ42, and widespread neurofibrillary pathology (Guardia-Laguarta et al., 2010).

In the Kurdish proband, a detailed neuropathological examination revealed extensive amyloid, tau, and α-synuclein pathology, but no deposits of TDP-43, FUS, or PrP. Amyloid pathology consisted of abundant cored and diffuse plaques throughout the cortex in addition to some cerebral amyloid angiopathy in the vasculature (CERAD stage C). Notably, N-truncated pyroglutamate-modified Aβ peptides were observed, including within Purkinje cells. Tau pathology consisted of neurofibrillary tangles, dystrophic neurites, and neuropil threads, especially prominent in the neocortex, hippocampal formation, and thalamus (Braak stage VI). Alpha-synuclein pathology was most prominent in the amygdala, temporal cortex, hippocampal formation, brainstem, and basal ganglia. The abundant Lewy body pathology in these regions was consistent with Parkinson's disease stage 6 (Braak et al., 2003) and fulfilled criteria for dementia with Lewy bodies (McKeith et al., 2005). Spongiosis was also observed in the superficial layers of the frontal and parietal cortices along with reactive astrogliosis (Sieczkowski et al., 2015).

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

Biological Effect

This variant has been shown to be pathogenic in mice. Comparing APP knockin mice expressing the Swedish mutation to knock-in mice expressing both the Swedish and Iberian mutations, APP NL-F knock-in, indicated the Iberian mutation boosts amyloid deposition, increases the Aβ42/Aβ40 ratio, and exacerbates synapse loss and cognitive impairment (Saito et al., 2014). I716F was also reported to interfere with presynaptic differentiation, reducing synaptogenesis in co-cultures of primary mouse neurons with transfected human embryonic kidney cells (Schilling et al., 2023). Moreover, synaptic loss and reduced longevity were observed in transgenic C. elegans co-expressing mutant I45F (Aβ numbering for I176F) with wildtype PSEN1, as described in a preprint (Devkota et al., 2023).

The molecular underpinnings of these effects have been examined in multiple studies. Even before this mutation was detected in a patient, an isoleucine to phenylalanine change at this position was shown experimentally to affect APP cleavage by γ-secretase. Specifically, it was shown that the amino acid change, referred to as I45F, affected γ-secretase cleavage specificity and caused a dramatic increase in the Aβ42/Aβ40 ratio, mostly due to a large decrease in Aβ40 production (Lichtenthaler et al., 1999). Consistent with this effect on Aβ production, an elevated Aβ42/Aβ40 ratio was reported in CHO cells as well as increased APP C-terminal fragments and decreased APP intracellular domain production (Herl et al., 2009; Guardia-Laguarta et al., 2010).

Subsequent detailed studies of APP processing suggest this mutation causes inefficient processing of Aβ peptides resulting in longer peptides, decreased total Aβ production, in particular Aβ40, and a possible switch between the two major pathways for producing Aβ peptides (Bolduc et al., 2016, Szaruga et al., 2017, Bhattarai et al., 2020, Devkota et al., 2021, Feb 2021 news, Schilling et al., 2023).

One possibility is that the mutation favors endoproteolysis at the ε site after L49 at the beginning of the Aβ49 → Aβ46 → Aβ43 → Aβ40 path, but the bulky phenylalanine blocks the Aβ46 → Aβ43 trimming step, inhibiting production of Aβ43 and its downstream product Aβ40 (Bolduc et al., 2016). Indeed, Szaruga and colleagues reported a destabilization of the γ-secretase-Aβ46 complex leading to dissociation and release of Aβ46 (Szaruga et al., 2017). At the same time, the substituted phenylalanine may enhance γ-cleavage at the Aβ42 site, which is normally part of the Aβ48 → Aβ45 → Aβ42 → Aβ38 path, resulting in a pathway switch (Bolduc et al., 2016). Interestingly, replacing hydrophylic lysine at position 28 with hydrophobic alanine in I45F peptides increased the proportion of Aβ38 produced and reduced that of Aβ42 (Koch et al., 2023, Nov 2023 news). The authors hypothesized K28A rescued substrate-enzyme destabilization by pushing the peptide further into the membrane, counteracting the hydrophilic pull of its N-terminus.

A cryo-electron microscopy study of PSEN1 bound to a fragment of APP suggested I716 lies within a substrate binding pocket (Zhou et al., 2019; Jan 2019 news). The authors speculated that this pocket is large enough to accommodate the aromatic side chain of I716F’s phenylalanine and may favor production of Aβ48 by stabilizing the APP conformation (although the latter proposal is not supported by the experiments described above). Moreover, a study using molecular dynamics simulations suggested I716, together with V715, serve to anchor APP at the PSEN1 internal docking site, a region distinct from the catalytic center, that is essential for substrate positioning and stabilization (Chen and Zacharias 2022).

As described in a preprint, it is possible that I45F, as well as other familial AD mutations, stall the γ-secretase-substrate complex and the presence of this membrane-anchored complex per se, rather than the release of Aβ peptides, is toxic (Devkota et al., 2023; Nov 2023 news). The co-expression of wildtype PSEN1 with either I45F, V44F/I45F, a double-mutant which completely blocks production of Aβ42, or V50F/M51F, a double-mutant that essentially blocks all Aβ production, led to synaptic loss.

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

This mutation has been introduced into several AD mouse models, including two knock-in models (APP^NL-F and APP^NL-G-F). The presence of the I716F mutation in these models significantly increases the ratio of Aβ42 to Aβ40_. These knock-in mice, which also harbor additional APP mutations, develop amyloid plaques, gliosis, and cognitive impairment, but not tangles or neurodegeneration. They are considered advantageous models for studying the effects of pathological levels of Aβ in the context of physiological levels of APP.

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References

Research Models Citations

1. APP NL-F Knock-in
2. APP NL-G-F Knock-in

Mutations Citations

1. APP K670_M671delinsNL (Swedish)

News Citations

1. Are the Long Aβ Peptides the Real Bad Guys? 5 Feb 2021
2. Patricidal Protein? Aβ42 said to Inhibit Its Parent, γ-Secretase 17 Nov 2023
3. CryoEM γ-Secretase Structures Nail APP, Notch Binding 11 Jan 2019

Paper Citations

1. Guerreiro RJ, Baquero M, Blesa R, Boada M, Brás JM, Bullido MJ, Calado A, Crook R, Ferreira C, Frank A, Gómez-Isla T, Hernández I, Lleó A, Machado A, Martínez-Lage P, Masdeu J, Molina-Porcel L, Molinuevo JL, Pastor P, Pérez-Tur J, Relvas R, Oliveira CR, Ribeiro MH, Rogaeva E, Sa A, Samaranch L, Sánchez-Valle R, Santana I, Tàrraga L, Valdivieso F, Singleton A, Hardy J, Clarimón J. Genetic screening of Alzheimer's disease genes in Iberian and African samples yields novel mutations in presenilins and APP. Neurobiol Aging. 2010 May;31(5):725-31. Epub 2008 Jul 30 PubMed.
2. Sieczkowski E, Milenkovic I, Venkataramani V, Giera R, Ströbel T, Höftberger R, Liberski PP, Auff E, Wirths O, Bayer TA, Kovacs GG. I716F AβPP Mutation Associates with the Deposition of Oligomeric Pyroglutamate Amyloid-β and α-Synucleinopathy with Lewy Bodies. J Alzheimers Dis. 2015 Jan 1;44(1):103-14. PubMed.
3. Guardia-Laguarta C, Pera M, Clarimón J, Molinuevo JL, Sánchez-Valle R, Lladó A, Coma M, Gómez-Isla T, Blesa R, Ferrer I, Lleó A. Clinical, neuropathologic, and biochemical profile of the amyloid precursor protein I716F mutation. J Neuropathol Exp Neurol. 2010 Jan;69(1):53-9. PubMed.
4. Braak H, Del Tredici K, Rüb U, De Vos RA, Jansen Steur EN, Braak E. Staging of brain pathology related to sporadic Parkinson's disease. Neurobiol Aging. 2003 Mar-Apr;24(2):197-211. PubMed.
5. McKeith IG, Dickson DW, Lowe J, Emre M, O'Brien JT, Feldman H, Cummings J, Duda JE, Lippa C, Perry EK, Aarsland D, Arai H, Ballard CG, Boeve B, Burn DJ, Costa D, del Ser T, Dubois B, Galasko D, Gauthier S, Goetz CG, Gomez-Tortosa E, Halliday G, Hansen LA, Hardy J, Iwatsubo T, Kalaria RN, Kaufer D, Kenny RA, Korczyn A, Kosaka K, Lee VM, Lees A, Litvan I, Londos E, Lopez OL, Minoshima S, Mizuno Y, Molina JA, Mukaetova-Ladinska EB, Pasquier F, Perry RH, Schulz JB, Trojanowski JQ, Yamada M. Diagnosis and management of dementia with Lewy bodies: third report of the DLB Consortium. Neurology. 2005 Dec 27;65(12):1863-72. PubMed.
6. Saito T, Matsuba Y, Mihira N, Takano J, Nilsson P, Itohara S, Iwata N, Saido TC. Single App knock-in mouse models of Alzheimer's disease. Nat Neurosci. 2014 May;17(5):661-3. Epub 2014 Apr 13 PubMed.
7. Schilling S, Pradhan A, Heesch A, Helbig A, Blennow K, Koch C, Bertgen L, Koo EH, Brinkmalm G, Zetterberg H, Kins S, Eggert S. Differential effects of familial Alzheimer's disease-causing mutations on amyloid precursor protein (APP) trafficking, proteolytic conversion, and synaptogenic activity. Acta Neuropathol Commun. 2023 Jun 1;11(1):87. PubMed.
8. 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. Alzheimer mutations stabilize synaptotoxic γ-secretase-substrate complexes. 10.1101/2023.09.08.556905 bioRxiv
9. Lichtenthaler SF, Wang R, Grimm H, Uljon SN, Masters CL, Beyreuther K. Mechanism of the cleavage specificity of Alzheimer's disease gamma-secretase identified by phenylalanine-scanning mutagenesis of the transmembrane domain of the amyloid precursor protein. Proc Natl Acad Sci U S A. 1999 Mar 16;96(6):3053-8. PubMed.
10. Herl L, Thomas AV, Lill CM, Banks M, Deng A, Jones PB, Spoelgen R, Hyman BT, Berezovska O. Mutations in amyloid precursor protein affect its interactions with presenilin/gamma-secretase. Mol Cell Neurosci. 2009 Jun;41(2):166-74. Epub 2009 Mar 9 PubMed.
11. Bolduc DM, Montagna DR, Seghers MC, Wolfe MS, Selkoe DJ. The amyloid-beta forming tripeptide cleavage mechanism of γ-secretase. Elife. 2016 Aug 31;5 PubMed.
12. 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.
13. Bhattarai A, Devkota S, Do HN, Wang J, Bhattarai S, Wolfe MS, Miao Y. Mechanism of Tripeptide Trimming of Amyloid β-Peptide 49 by γ-Secretase. J Am Chem Soc. 2022 Apr 13;144(14):6215-6226. Epub 2022 Apr 4 PubMed. Correction.
14. Devkota S, Williams TD, Wolfe MS. Familial Alzheimer's disease mutations in amyloid protein precursor alter proteolysis by γ-secretase to increase amyloid β-peptides of ≥45 residues. J Biol Chem. 2021;296:100281. Epub 2021 Jan 12 PubMed.
15. Koch M, Enzlein T, Chen SY, Petit D, Lismont S, Zacharias M, Hopf C, Chávez-Gutiérrez L. APP substrate ectodomain defines amyloid-β peptide length by restraining γ-secretase processivity and facilitating product release. EMBO J. 2023 Dec 1;42(23):e114372. Epub 2023 Oct 18 PubMed.
16. 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.
17. Chen SY, Zacharias M. An internal docking site stabilizes substrate binding to γ-secretase: Analysis by molecular dynamics simulations. Biophys J. 2022 Jun 21;121(12):2330-2344. Epub 2022 May 20 PubMed.

Further Reading

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