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Published on: November 22, 2024
Microvascular ultrastructural changes precede cognitive impairment in the murine APPswe/PS1dE9 model of Alzheimer's
Patricia Kelly1, Paul Denver1, Simon C Satchell2
1School of Biomedical Sciences, University of Ulster, Coleraine, Northern Ireland, UK.
Abstract:
Cerebral and systemic organ microvascular pathologies coexist with human Alzheimer's disease (AD) neuropathology. In this study, we hypothesised that both cerebral and systemic microvascular pathologies exist in 4- to 5-month-old male APPswe/PS1dE9 (APP/PS1) transgenic mice prior to the onset of cognitive impairment. To assess this we examined recognition memory in both wild-type and APP/PS1 mice using the object recognition task (ORT; n = 11 per group) and counted thioflavin-S-positive plaques in brain (n = 6 per group). Vascular casts of brain, liver, spleen and kidneys were examined using scanning electron microscopy (n = 6 per group), and the urinary albumin-to-creatinine ratio (uACR; n = 5 per group) was measured as an index of glomerular permeability. Murine recognition memory was intact, as demonstrated by a significant preference for the novel object in the ORT paradigm. Brain sections of wild-type mice were devoid of thioflavin-S positivity, whereas age-matched APP/PS1 mice had an average of 0.88 ± 0.22 thioflavin-S-positive plaques in the cortex, 0.42 ± 0.17 plaques in the dentate gyrus and 0.30 ± 0.07 plaques in the cornus ammonis 1 region. The profiles of casted cerebral capillaries of wild-type mice were smooth and regular in contrast to those of APP/PS1 mice which demonstrate characteristic (0.5-4.6 μm) 'tags'. APP/PS1 mice also had a significantly reduced hepatic vessel number (p = 0.0002) and an increase in the number of splenic microvascular pillars (p = 0.0231), in the absence of changes in either splenic microvascular density (p = 0.3746) or glomerular ultrastructure. The highly significant reduction in uACR in APP/PS1 mice compared to wild-type (p = 0.0079) is consistent with glomerular microvascular dysfunction. These findings highlight early microvascular pathologies in 4- to 5-month-old APP/PS1 transgenic mice and may indicate an amenable target for pharmacological intervention in AD.
Insights
Early microvascular changes in Alzheimer's disease (AD) models occur before cognitive decline. This study in APP/PS1 mice reveals cerebral and systemic microvascular pathologies, suggesting potential therapeutic targets for AD.
Area of Science:
- Neuroscience
- Pathology
- Vascular Biology
Background:
- Alzheimer's disease (AD) is characterized by neuropathology and co-occurring cerebral and systemic microvascular pathologies.
- Early detection of microvascular dysfunction is crucial for understanding AD pathogenesis and developing interventions.
Purpose of the Study:
- To investigate the presence of cerebral and systemic microvascular pathologies in young male APPswe/PS1dE9 (APP/PS1) transgenic mice before the onset of cognitive impairment.
- To correlate these pathologies with early AD markers.
Main Methods:
- Object recognition task (ORT) to assess recognition memory in APP/PS1 and wild-type mice.
- Thioflavin-S staining to quantify amyloid plaques in brain sections.
- Scanning electron microscopy of vascular casts (brain, liver, spleen, kidneys).
- Measurement of urinary albumin-to-creatinine ratio (uACR) as an indicator of glomerular permeability.
Main Results:
- APP/PS1 mice showed intact recognition memory but exhibited early amyloid plaques in the brain.
- Cerebral capillaries in APP/PS1 mice displayed characteristic 'tags', unlike smooth wild-type capillaries.
- Significant reduction in hepatic vessel number and increased splenic microvascular pillars were observed in APP/PS1 mice.
- A significant reduction in uACR indicated glomerular microvascular dysfunction in APP/PS1 mice.
Conclusions:
- Four- to five-month-old APP/PS1 mice exhibit distinct cerebral and systemic microvascular pathologies prior to cognitive deficits.
- These early microvascular alterations represent potential therapeutic targets for Alzheimer's disease intervention.
