Correlative Memory Deficits, Aβ Elevation, and Amyloid Plaques in Transgenic Mice
Abstract
Transgenic mice overexpressing the 695-amino acid isoform of human Alzheimer beta-amyloid (Abeta) precursor protein containing a Lys670 --> Asn, Met671 --> Leu mutation had normal learning and memory in spatial reference and alternation tasks at 3 months of age but showed impairment by 9 to 10 months of age. A fivefold increase in Abeta(1-40) and a 14-fold increase in Abeta(1-42/43) accompanied the appearance of these behavioral deficits. Numerous Abeta plaques that stained with Congo red dye were present in cortical and limbic structures of mice with elevated amounts of Abeta. The correlative appearance of behavioral, biochemical, and pathological abnormalities reminiscent of Alzheimer's disease in these transgenic mice suggests new opportunities for exploring the pathophysiology and neurobiology of this disease.
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APP transgenic mouse models have elevated inflammation markers and gliosis associated with amyloid deposits.
“Similar to AD, APP transgenic mouse models have elevated inflammation markers and gliosis associated with amyloid deposits (Games et al., 1995; Hsiao et al., 1996; Sturchler-Pierrat et al., 1997).”
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 Hsiao et al., 1996
The well established Tg2576 mouse model of AD, which overexpresses APP with the Swedish mutation, was used as a control and makes slightly more APP than the highest expressing 5XFAD line, Tg6799.
“The well established Tg2576 mouse model of AD, which overexpresses APP with the Swedish mutation (Hsiao et al., 1996), was used as a control in these studies and makes slightly more APP than our highest expressing line, Tg6799.”
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 Hsiao et al., 1996
Tg2576 mice did not begin to deposit amyloid until ~9-12 months of age.
“In contrast, Tg2576 mice did not begin to deposit amyloid until ∼ 9-12 months of age (data not shown) (Hsiao et al., 1996).”
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 Hsiao et al., 1996
The first successful mouse models reproducing Aβ pathologies overexpressed human APP with either a single Swedish or Indiana mutation.
“The first successful mouse models reproducing Aβ pathologies overexpressed human APP with either a single Swedish [25, 26] or Indiana [27] mutation.”
From Amyloid-β plaque formation and reactive gliosis are required for induction of cognitive deficits in App knock-in mouse models of Alzheimer’s disease (2019) · cites this paper as [25]
Tg2576 mice develop age-dependent behavioral deficits as assessed by Y maze, T maze, and Morris water maze testing.
“In addition, Tg2576 mice develop agedependent behavioral deficits as assessed by Y maze, T maze, and Morris water maze testing (Hsiao et al., 1996;Chapman et al., 1999;Westerman et al., 2000).”
From Age-Dependent Changes in Brain, CSF, and Plasma Amyloid β Protein in the Tg2576 Transgenic Mouse Model of Alzheimer's Disease (2001) · cites this paper as Hsiao et al., 1996
The Tg2576 mouse model expresses the Swedish mutation of APP at high level under control of the hamster prion protein promoter.
“The Tg2576 mouse model of Alzheimer's disease (Hsiao et al., 1996) expresses the Swedish mutation of APP (APP K670N,M671L ) at high level under control of the hamster prion protein (PrP) promoter.”
From Age-Dependent Changes in Brain, CSF, and Plasma Amyloid β Protein in the Tg2576 Transgenic Mouse Model of Alzheimer's Disease (2001) · cites this paper as Hsiao et al., 1996
Tg2576 overexpresses a mutant form of APP (isoform 695) with the Swedish mutation (KM670/671NL), resulting in elevated levels of amyloid beta (Aβ) and ultimately amyloid plaques.
“It overexpresses a mutant form of APP (isoform 695) with the Swedish mutation (KM670/671NL), resulting in elevated levels of amyloid beta (Aβ) and ultimately amyloid plaques [31].”
The observed relationship between VEEV TC-83 infection and the progression of AD may contribute to the development of AD, leading to elevated levels of Aβ and the formation of amyloid plaques.
“The observed relationship between VEEV TC-83 infection and the progression of AD may contribute to the development of AD, leading to elevated levels of Aβ and the formation of amyloid plaques [31].”
The Tg2576 model is one of the most well characterized and widely used mouse models of AD.
“The Tg2576 model is one of the most well characterized and widely used mouse models of AD.”
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 Hsiao et al., 1996
This progression is different from Tg2576, which manifests synaptic damage at an early stage (4.5 months) with a corresponding decrease in synaptic density markers prior to Aβ plaque development (10 months) and cognitive deficiencies (one year).
“This is different from the progression in Tg2576, which manifests synaptic damage at an early stage of pathological development (4.5 months) [68,69] with a corresponding decrease in synaptic density markers [70] prior to Aβ plaque development (10 months) [71] and cognitive deficiencies (one year) [72,73].”
From Centella Asiatica Improves Memory and Promotes Antioxidative Signaling in 5XFAD Mice (2019) · cites this paper as [71]
Tg2576 transgenic mice overexpress human APP695 with the Swedish mutation (APPswe) and show behavioural and histopathological abnormalities that closely mimic early AD.
“Tg2576 transgenic mice overexpressing the human APP695 protein with the ‘Swedish' mutation (APPswe), which show behavioural and histopathological abnormalities that closely mimic early AD21.”
From Dopamine neuronal loss contributes to memory and reward dysfunction in a model of Alzheimer’s disease (2017) · cites this paper as [21]
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- Authors
- Hsiao, K., Chapman, P., Nilsen, S., Eckman, C., Harigaya, Y., Younkin, S., Yang, F., & Cole, G.
- Affiliations
- University of Minnesota (US)
- University of Wales (GB)
- Mayo Clinic in Florida (US)
- University of California, Los Angeles (US)
- Corresponding author
- Hsiao, Karen
- Venue
- Science
- Published
- 1996-10-04
- Volume
- 274
- Issue
- 5284
- Pages
- 99-103
- ISSN
- 0036-8075 (ISSN-L)
- 1095-9203
- OpenAlex
- W2001210466
- Cited by
- 4,210
- References
- 23
- Citations by year
- 2026: 39 · 2025: 69 · 2024: 106 · 2023: 78 · 2022: 98 · 2021: 111 · 2020: 122 · 2019: 114 · 2018: 112 · 2017: 125 · 2016: 130 · 2015: 132 · 2014: 156 · 2013: 200 · 2012: 186
- FWCI
- 67.65
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Science (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r01ag009009-07)
- National Institute on Aging (AG06656, AG9009, R01AG006656)
- 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, memory impairment, amyloid-beta, amyloid plaques, APP transgenic mice, APP695, Aβ(1-40), amyloid-beta 42, spatial learning, Congo red staining
- MeSH terms
- Aging, Alzheimer Disease, Animals, Brain, Brain Chemistry, Learning Disabilities, Memory Disorders, Mice, Transgenic, Peptide Fragments, Psychomotor Performance, Amyloid beta-Peptides, Amyloid beta-Protein Precursor, Maze Learning, Mice
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