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Cited by 1,386Alzheimer's disease research and treatmentsDementia and Cognitive Impairment ResearchNeuroinflammation and Neurodegeneration Mechanisms

Accelerated Alzheimer-type phenotype in transgenic mice carrying both mutant amyloid precursor protein and presenilin 1 transgenes

Holcomb, Leigh, Gordon, Marcia N., McGowan, Eileen, Yu, Xin, Benkovic, Stan, Jantzen, Paul, Wright, Kristal, Saad, Irene +11 more·1998·Nature Medicine
DOI 10.1038/nm0198-097
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Abstract

Genetic causes of Alzheimer's disease (AD) include mutations in the amyloid precursor protein (APP), presenilin 1 (PS1), and presenilin 2 (PS2) genes. The mutant APP(K670N,M671L) transgenic line, Tg2576, shows markedly elevated amyloid beta-protein (A beta) levels at an early age and, by 9-12 months, develops extracellular AD-type A beta deposits in the cortex and hippocampus. Mutant PS1 transgenic mice do not show abnormal pathology, but do display subtly elevated levels of the highly amyloidogenic 42- or 43-amino acid peptide A beta42(43). Here we demonstrate that the doubly transgenic progeny from a cross between line Tg2576 and a mutant PS1M146L transgenic line develop large numbers of fibrillar A beta deposits in cerebral cortex and hippocampus far earlier than their singly transgenic Tg2576 littermates. In the period preceding overt A beta deposition, the doubly transgenic mice show a selective 41% increase in A beta42(43) in their brains. Thus, the development of AD-like pathology is substantially enhanced when a PS1 mutation, which causes a modest increase in A beta42(43), is introduced into Tg2576-derived mice. Remarkably, both doubly and singly transgenic mice showed reduced spontaneous alternation performance in a "Y" maze before substantial A beta deposition was apparent. This suggests that some aspects of the behavioral phenotype in these mice may be related to an event that precedes plaque formation.

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Crossref · 10.1038/nm0198-097

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  • Mice coexpressing FAD mutant APP and PS1 transgenes exhibit additive increases in Aβ42 production.

    “Previous studies have shown that mice coexpressing FAD mutant APP and PS1 transgenes exhibit additive increases in A 𝛃 42 production (Borchelt et al., 1996, 1997; Citron et al., 1997; Holcomb et al., 1998), althoughrarely have more than two A 𝛃 42 -elevating FAD mutations been combined in transgenic animals.”

    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 Holcomb et al., 1998

  • Increasing Aβ by expressing FAD mutant PS1 together with FAD mutant APP failed to produce substantial enhancements of the behavioral deficits observed in mice overexpressing FAD mutant APP alone.

    “Our findings are also consistent with research showing that increasing Ab by expressing FAD mutant PS1 together with FAD mutant APP failed to produce substantial enhancements of the behavioral deficits observed in mice overexpressing FAD mutant APP alone (56)(57)(58).”

    From Amyloid precursor protein-induced axonopathies are independent of amyloid-β peptides (2008) · cites this paper as [57]

  • Formation of these defects was enhanced by genetic reductions in kinesin-1 in Drosophila and in mice, where increased Aβ42/Aβ40 ratios and enhanced amyloid deposition were also observed.

    “Formation of these defects was shown to be enhanced by genetic reductions in kinesin-1 in Drosophila (29,30) and in mice, where increased Ab42/Ab40 ratios and enhanced amyloid deposition were also observed (7,57).”

    From Amyloid precursor protein-induced axonopathies are independent of amyloid-β peptides (2008) · cites this paper as [57]

  • Aβ plaques have been detected in the retina of transgenic mouse models of AD.

    “Aβ plaques have also been detected in the retina of transgenic mouse models of AD (APPswe / PS1ΔE9, Tg2576AD, 3xTg-AD, PSAPP, 5xFAD; Hsiao et al., 1996; Holcomb et al., 1998; Takeuchi et al., 2000; Lukiw et al., 2001; Oddo et al., 2003; Kumar-Singh et al., 2005; Oakley et al., 2006; Philipson et al., 2010; Koronyo-Hamaoui et al., 2011).”

    From The role of microglia in retinal neurodegeneration: Alzheimer’s disease, parkinson, and glaucoma. (2017) · cites this paper as Holcomb et al., 1998

  • AD transgenic mice showed physiological and neuritic alterations prior to plaques.

    “AD transgenic mice showed physiological [32, 74, 77, 124] and neuritic alterations [22, 125] prior to plaques”

    From Intraneuronal β-amyloid accumulation and synapse pathology in Alzheimer’s disease (2010) · cites this paper as [74]

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Authors
Holcomb, L., Gordon, M. N., McGowan, E., Yu, X., Benkovic, S., Jantzen, P., Wright, K., Saad, I., Mueller, R., Morgan, D., Sanders, S., Zehr, C., O'Campo, K., Hardy, J., Prada, C.-M., Eckman, C., Younkin, S., Hsiao, K., & Duff, K.
Affiliations
  • University of South Florida (US)
  • Mayo Clinic in Florida (US)
  • University of Minnesota (US)
  • Mayo Clinic (US)
Corresponding author
Duff, Karen
ORCID
Venue
Nature Medicine
Publisher
Springer Science and Business Media LLC
Published
1998-01
Volume
4
Issue
1
Pages
97-100
ISSN
  • 1078-8956 (ISSN-L)
  • 1546-170X
DOI
10.1038/nm0198-097
OpenAlex
W2077464099
Cited by
1,386
References
22
Citations by year
2026: 16 · 2025: 24 · 2024: 40 · 2023: 33 · 2022: 26 · 2021: 39 · 2020: 36 · 2019: 39 · 2018: 32 · 2017: 46 · 2016: 36 · 2015: 42 · 2014: 45 · 2013: 53 · 2012: 72
FWCI
35.37
Type
journal article
Language
en
Open access
closed
Licence
www.springer.com/tdm (tdm)
Locations
  • Nature Medicine (publishedVersion)
  • PubMed (publishedVersion)
  • UCL Discovery (University College London) (submittedVersion)
Funders
  • National Institute on Aging (AG 146133)
  • National Institute of Neurological Disorders and Stroke (NS33249, R01NS033249)
Topics
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
  • Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
  • Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
Keywords
Alzheimer's disease, amyloid precursor protein, presenilin 1, Tg2576 mice, amyloid-beta, amyloid plaques, double transgenic mice, behavioral phenotypes, spatial learning, hippocampus, cerebral cortex
MeSH terms
Alzheimer Disease, Analysis of Variance, Animals, Brain, Cerebral Cortex, Crosses, Genetic, Genotype, Glial Fibrillary Acidic Protein, Humans, Membrane Proteins, Mice, Transgenic, Motor Activity, Posture, Psychomotor Performance, Reflex, Seizures, Amyloid beta-Protein Precursor, Mice, Presenilin-1

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