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Preparation of Acute Hippocampal Slices from Rats and Transgenic Mice for the Study of Synaptic Alterations during Aging and Amyloid Pathology
Published on: March 23, 2011
Age-dependent alterations of the hippocampal cell composition and proliferative potential in the hAβPPSwInd-J20 mouse
YuHong Fu1, Zoltán Rusznák2, John B J Kwok1
1Neuroscience Research Australia, Sydney, NSW, Australia School of Medical Science, The University of New South Wales, Sydney, NSW, Australia.
Abstract:
The J20 mouse expresses human mutant amyloid-β protein precursor (hAβPPSwInd) and is an established transgenic model of Alzheimer's disease (AD). From the age of 5 months, amyloid-β (Aβ) deposits appear in the hippocampus with concomitant increase of AD-associated features. Although changes occurring after the appearance of Aβ deposits have been extensively studied, very little is known about alterations that occur prior to 5 months. The present study aimed to identify changes in the cellular composition and proliferative potential of the J20 hippocampus using 1-18-month-old mice. Neuronal, non-neuronal, Ki-67+, and TUNEL+ cell numbers were counted with the isotropic fractionator method. Age-dependent changes of the expression of microglia-, astrocyte-, and neurogenesis-specific markers were sought in the entire hippocampus. Several transgene-associated changes were revealed before the appearance of Aβ deposits. The number of proliferating cells decreased whereas the number of microglia clusters increased as early as 4 weeks of age. The neurogenesis was also impaired in the dentate gyrus of 7-11-week-old J20 mice. A statistically significant negative correlation was found between the number of proliferating cells and age in both populations, but the time course of the age-dependence was steeper in wild-type than in J20 mice. Negative age-dependence was noted when the number of cells committed to apoptosis was examined. Our results indicate that overexpression of mutant hAβPP initiates a cascade of pathologic events well before the appearance of visible Aβ plaques. Accordingly, early signs of AD include reduced cell proliferation, impaired neurogenesis, and increased activity of microglia in the hippocampus.
Insights
Early Alzheimer's disease (AD) signs in J20 mice include reduced cell proliferation and impaired neurogenesis, occurring before amyloid-β (Aβ) deposits appear. Mutant human amyloid-β protein precursor (hAβPP) overexpression triggers these early pathological events.
Area of Science:
- Neuroscience
- Genetics
- Pathology
Background:
- The J20 mouse model overexpresses human mutant amyloid-β protein precursor (hAβPP) and exhibits Alzheimer's disease (AD) features.
- Amyloid-β (Aβ) deposits and AD-associated changes emerge in J20 mice around 5 months of age.
- Pre-plaque pathological alterations in the J20 mouse hippocampus remain largely uncharacterized.
Purpose of the Study:
- To investigate cellular composition and proliferative capacity changes in the J20 mouse hippocampus before Aβ deposition.
- To identify early, transgene-associated alterations in the J20 mouse model of Alzheimer's disease.
Main Methods:
- Utilized the isotropic fractionator method to quantify neuronal, non-neuronal, proliferating (Ki-67+), and apoptotic (TUNEL+) cells in J20 mice aged 1-18 months.
- Assessed age-dependent expression of microglia, astrocyte, and neurogenesis markers throughout the hippocampus.
- Correlated cell proliferation rates with age and apoptosis markers.
Main Results:
- Reduced cell proliferation and increased microglia cluster formation observed as early as 4 weeks of age in J20 mice.
- Impaired neurogenesis detected in the dentate gyrus of 7-11-week-old J20 mice.
- A steeper age-dependent decline in cell proliferation was noted in wild-type compared to J20 mice, with increased apoptosis in J20 mice.
Conclusions:
- Overexpression of mutant hAβPP initiates a cascade of pathological events preceding visible Aβ plaque formation.
- Early indicators of Alzheimer's disease in this model include diminished cell proliferation, compromised neurogenesis, and heightened microglial activity.
- These findings highlight the importance of studying pre-plaque stages in Alzheimer's disease pathogenesis.
