Characterization of a 3xTg-AD mouse model of Alzheimer's disease with the senescence accelerated mouse prone 8 (SAMP8) background

Synapse. 2018 Apr;72(4). doi: 10.1002/syn.22025. Epub 2018 Feb 1.


No model fully recapitulates the neuropathology of Alzheimer's disease (AD). Although the triple-transgenic mouse model of AD (3xTg-AD) expresses Aβ plaques and tau-laden neurofibrillary tangles, as well as synaptic and behavioral deficits, it does not display frank neuronal loss. Because old age is the most important risk factor in AD, senescence-related interactions might be lacking to truly establish an AD-like environment. To investigate this hypothesis, we bred the 3xTg-AD mouse with the senescence-accelerated mouse prone 8 (SAMP8), a model of accelerated aging. We generated four groups of heterozygous mice with either the SAMP8 or SAMR1 (senescence-resistant-1) genotype, along with either the 3xTg-AD or non-transgenic (NonTg) genotype. Despite no differences among groups in total latency to escape the Barnes maze, a greater number of errors were noticed before entering the target hole in 19-month-old P8/3xTg-AD mice at day 5, compared to other groups. Postmortem analyses revealed increased cortical levels of phospho-tau (Thr231) in female P8/3xTg-AD mice (+277% vs. R1/3xTg-AD mice), without other tau-related changes. Female P8/3xTg-AD mice exhibited higher cortical soluble Aβ40 and Aβ42 concentrations (Aβ40, +85%; Aβ42, +35% vs. R1/3xTg-AD), whereas insoluble forms remained unchanged. Higher Aβ42 load coincided with increased astroglial activation in female P8/3xTg-AD mice, as measured with glial fibrillary acidic protein (GFAP) (+57% vs. R1/3xTg-AD mice). To probe neuronal degeneration, concentrations of neuronal nuclei (NeuN) were measured, but no differences were detected between groups. Altogether, the SAMP8 genotype had deleterious effects on spatial memory and exerted female-specific aggravation of AD neuropathology without overt neurodegeneration in 3xTg-AD mice.

Keywords: Alzheimer's disease; astrogliosis; brain aging; cerebral amyloidosis; tauopathy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alzheimer Disease* / metabolism
  • Alzheimer Disease* / pathology
  • Alzheimer Disease* / psychology
  • Amyloid beta-Peptides / metabolism
  • Amyloid beta-Protein Precursor / genetics
  • Amyloid beta-Protein Precursor / metabolism
  • Animals
  • Anxiety / metabolism
  • Anxiety / pathology
  • Apolipoproteins E / metabolism
  • Body Weight / physiology
  • Cerebral Cortex / metabolism
  • Cerebral Cortex / pathology
  • Disease Models, Animal*
  • Female
  • Glial Fibrillary Acidic Protein / metabolism
  • Gliosis / metabolism
  • Gliosis / pathology
  • Humans
  • Mice, 129 Strain
  • Mice, Inbred C57BL
  • Mice, Transgenic*
  • Motor Activity / physiology
  • Peptide Fragments / metabolism
  • Spatial Memory / physiology
  • Species Specificity
  • tau Proteins / genetics
  • tau Proteins / metabolism


  • APP protein, human
  • Amyloid beta-Peptides
  • Amyloid beta-Protein Precursor
  • Apolipoproteins E
  • Glial Fibrillary Acidic Protein
  • MAPT protein, human
  • Mapt protein, mouse
  • Peptide Fragments
  • amyloid beta-protein (1-40)
  • amyloid beta-protein (1-42)
  • glial fibrillary astrocytic protein, mouse
  • tau Proteins