A New Pathogenic Mutation in the APP Gene (I716V) Increases the Relative Proportion of A 42(43)
Abstract
We report a novel mutation in the amyloid precursor protein gene (APP I716V) which probably leads to familial early onset Alzheimer's disease with an onset age in the mid 50s. Cells transfected with cDNAs bearing this mutation produce more A beta 1-42(43) than those transfected with wild-type APP and this effect is additive with that of the previously reported APP V717I mutation thus providing a novel approach for further increasing A beta 1-42(43) in model systems.
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Intramolecular combination of I716V and V717I mutations within APP doubled Aβ42 production compared with the individual mutations.
“In particular, the intramolecular combination of I716V and V717I mutations within APP doubled A 𝛃 42 production compared with the individual mutations (Eckman et al., 1997), as did the two PS1 FAD mutations M146L and L286V when introduced together into PS1 (Citron et al., 1998).”
From Intraneuronal β-Amyloid Aggregates, Neurodegeneration, and Neuron Loss in Transgenic Mice with Five Familial Alzheimer's Disease Mutations: Potential Factors in Amyloid Plaque Formation (2006) · cites this paper as Eckman et al., 1997
The Results and Discussion report that an APP construct combining I716V and V717I increased the Aβ1-42(43)-to-Aβ1-40 ratio compared with either mutation alone. Table 1 does not show a doubling of absolute Aβ42 production over both individual mutants; the paper’s approximately twofold result instead compares the ratio for I716V alone with wild-type APP. (LLM, conf=0.89)
Experimental — accuracy not yet measuredIntraneuronal Aβ42 plays a role in neurodegenerative processes relevant to AD.
“The accumulation of intraneuronal Aβ42 has been observed in the brains of AD patients and APP transgenic mice, and studies suggest that intraneuronal Aβ42 plays a role in neurodegenerative processes relevant to AD (reviewed in [7-9]).”
From Neuron loss in the 5XFAD mouse model of Alzheimer’s disease correlates with intraneuronal Aβ42 accumulation and Caspase-3 activation (2013) · cites this paper as [9]
The Introduction links elevated Aβ42(43) to mutations causing familial Alzheimer’s disease, and the Results and Discussion report increased Aβ42(43) in a mutation carrier. But the paper describes extracellular and plasma Aβ42(43), not intraneuronal accumulation or its role in neurodegenerative processes. (LLM, conf=0.83)
Experimental — accuracy not yet measuredFAD mutations in APP near the β- and γ-secretase cleavage sites either elevate total Aβ production (Swedish K670N/M671L) or increase Aβ42 generation specifically (Florida I716V and London V717I).
“FAD mutations in APP that cluster near the 𝛃 - and 𝛄 -secretase cleavage sites either elevate the production of total A 𝛃 , as is the case with the K670N/ M671L substitution [Swedish mutation (Mullan et al., 1992a)], or increase the generation of A 𝛃 42 specifically, as occurs with the I716V [Florida mutation (Eckman et al., 1997)] and V717I [London mutation (Goate et al., 1991)] substitutions.”
From Intraneuronal β-Amyloid Aggregates, Neurodegeneration, and Neuron Loss in Transgenic Mice with Five Familial Alzheimer's Disease Mutations: Potential Factors in Amyloid Plaque Formation (2006) · cites this paper as Eckman et al., 1997
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- Authors
- Eckman, C. B., Mehta, N. D., Crook, R., Perez-tur, J., Prihar, G., Pfeiffer, E., Graff-Radford, N., Hinder, P., Yager, D., Zenk, B., Refolo, L. M., Mihail Prada, C., Younkin, S. G., Hutton, M., & Hardy, J.
- Affiliations
- Mayo Clinic (US)
- University of South Florida (US)
- Corresponding author
- Hardy, J.
- Venue
- Human Molecular Genetics
- Publisher
- Oxford University Press (OUP)
- Published
- 1997-11-01
- Volume
- 6
- Issue
- 12
- Pages
- 2087-2089
- ISSN
- 0964-6906 (ISSN-L)
- 1460-2083
- OpenAlex
- W2142616340
- Cited by
- 236
- References
- 13
- Citations by year
- 2026: 8 · 2025: 6 · 2024: 7 · 2023: 5 · 2022: 4 · 2021: 6 · 2020: 14 · 2019: 11 · 2018: 9 · 2017: 9 · 2016: 3 · 2015: 9 · 2014: 13 · 2013: 8 · 2012: 2
- FWCI
- 6.10
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Human Molecular Genetics (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health
- Topics
- Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Health Sciences › Medicine › Neurology › Amyotrophic Lateral Sclerosis Research
- Keywords
- amyloid precursor protein, amyloid-beta 42, early-onset familial Alzheimer's disease, Alzheimer's disease pathogenesis
- MeSH terms
- Alzheimer Disease, Female, Humans, Middle Aged, Peptide Fragments, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Point Mutation, Age of Onset
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