Intraneuronal β-Amyloid Aggregates, Neurodegeneration, and Neuron Loss in Transgenic Mice with Five Familial Alzheimer's Disease Mutations: Potential Factors in Amyloid Plaque Formation

By Holly Oakley, Sarah L. Cole, Sreemathi Logan, E. Maus, Peizhen Shao, J. Craft, Angela L. Guillozet-Bongaarts, M. Ohno, J. Disterhoft, Linda J Van Eldik and 2 more. Journal of Neuroscience, 2006

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Mutations in the genes for amyloid precursor protein (APP) and presenilins (PS1, PS2) increase production of β-amyloid 42 (Aβ42) and cause familial Alzheimer's disease (FAD). Transgenic mice that express FAD mutant APP and PS1 overproduce Aβ42 and exhibit amyloid plaque pathology similar to that found in AD, but most transgenic models develop plaques slowly. To accelerate plaque development and investigate the effects of very high cerebral Aβ42 levels, we generated APP/PS1 double transgenic mice that coexpress five FAD mutations (5XFAD mice) and additively increase Aβ42 production. 5XFAD mice generate Aβ42 almost exclusively and rapidly accumulate massive cerebral Aβ42 levels. Amyloid deposition (and gliosis) begins at 2 months and reaches a very large burden, especially in subiculum and deep cortical layers. Intraneuronal Aβ42 accumulates in 5XFAD brain starting at 1.5 months of age (before plaques form), is aggregated (as determined by thioflavin S staining), and occurs within neuron soma and neurites. Some amyloid deposits originate within morphologically abnormal neuron soma that contain intraneuronal Aβ. Synaptic markers synaptophysin, syntaxin, and postsynaptic density-95 decrease with age in 5XFAD brain, and large pyramidal neurons in cortical layer 5 and subiculum are lost. In addition, levels of the activation subunit of cyclin-dependent kinase 5, p25, are elevated significantly at 9 months in 5XFAD brain, although an upward trend is observed by 3 months of age, before significant neurodegeneration or neuron loss. Finally, 5XFAD mice have impaired memory in the Y-maze. Thus, 5XFAD mice rapidly recapitulate major features of AD amyloid pathology and may be useful models of intraneuronal Aβ42-induced neurodegeneration and amyloid plaque formation.

Subfields: Cellular and Molecular Neuroscience, Molecular Biology, Physiology

View Paper: https://www.semanticscholar.org/paper/df73919e97d45599303916f09fd95b7c343ea8c8

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Citations in the corpus

APP processing in Alzheimer's disease (2011, result): “Studies with transgenic mouse models consistently confirm these results, revealing intracellular Ab accumulation as an early event in the neuropathological phenotype with decreasing intraneuronal levels of Ab as extracellular plaques build up [150-152].”
The Amyloid-β Oligomer Hypothesis: Beginning of the Third Decade (2018, background): “A Os and plaques in these mice begin to accumulate extensively around 2 months of age [11, 92, 95].”
Eliminating microglia in Alzheimer's mice prevents neuronal loss without modulating amyloid-β pathology. (2016, methodology): “The 5xfAD mice represent an aggressive model of amyloid pathologies, with amyloid-b plaques first depositing from 2 months of age (Oakley et al., 2006).”
A Unique Microglia Type Associated with Restricting Development of Alzheimer's Disease. (2017, positive): “Neuronal loss and deficits in spatial learning initiate at around 6 months and severe cognitive dysfunction is observed at 7–8 months of age (Kimura and Ohno, 2009; Oakley et al., 2006).”
Amyloid beta, mitochondrial dysfunction and synaptic damage: implications for cognitive decline in aging and Alzheimer's disease. (2008, background): “In addition, several studies of transgenic AD mice reported that intracellular Aβ accumulates early in AD progression [22,25–27].”
TREM2 lipid sensing sustains microglia response in an Alzheimer’s disease model (2015, positive): “We also found that the loss of layer-V neurons, a feature of 5XFAD mice (Eimer and Vassar, 2013; Oakley et al., 2006), was more prominent in Trem2−/−5XFAD mice (Fig.”
Alzheimer’s disease: experimental models and reality (2017, background): “The other major limitation of these mouse models was that while some showed evidence of localized hyperphosphorylated tau that may represent “pretangles” [107, 118, 151, 159], none developed neurofibrillary tangles.”
An epigenetic blockade of cognitive functions in the neurodegenerating brain (2012, background): “This neurodegeneration-associated increase of HDAC2 was confirmed in another mouse model of Alzheimer’s-disease-related pathologies and cognitive decline, the 5XFAD mous”
APP mouse models for Alzheimer's disease preclinical studies (2017, positive): “Oakley et al (2006) generated 5XFAD mice carrying five FAD mutations in APP and PS1 transgenes (APP K670N/M671L/I716V/V717I Tg and PSEN1 M146L/L286V Tg) driven by the Thy-1 promoter.”