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Basic Science and Pathogenesis
Ashley M Carey1, Silvia Fossati2
1Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA.
Insights
Hypoxia and low glucose worsen amyloid-beta
Area of Science:
- Neuroscience and Vascular Biology
- Molecular Mechanisms of Disease
Background:
- Alzheimer's Disease (AD) involves early disruptions in brain blood flow (hemodynamics) and damage, leading to cerebral hypoperfusion.
- Cardiovascular risk factors often cause hypoperfusion, exacerbating AD progression by affecting cerebral endothelial cells (ECs).
- Amyloid-beta (Aβ) peptides, particularly AβQ22 and Aβ42, are known to impair ECs, but their combined effect with hypoperfusion is unclear.
Purpose of the Study:
- To investigate how amyloid-beta (Aβ) peptides affect cerebral endothelial cells (ECs) under hypoperfusion conditions.
- To determine if combined Aβ exposure and hypoperfusion potentiate EC dysfunction via common molecular pathways.
- To identify specific molecular targets for treating vascular pathology in comorbid AD and hypoperfusion.
Main Methods:
- Human cerebral ECs were exposed to Aβ40-Q22 or Aβ42 under conditions simulating glucose deprivation (GD) and/or hypoxia.
- Evaluated cell death (apoptosis/necrosis), barrier integrity (TEER, BBB proteins), and angiogenesis (VEGF signaling).
- Assessed specific molecular markers including caspases, MMP2, ICAM1, IL-6, IL-8, IFNγ, IL-12p70, and ZO1.
Main Results:
- Combined Aβ and hypoperfusion significantly increased EC death, barrier dysfunction, inflammation, and impaired wound healing.
- AβQ22 exacerbated apoptosis and barrier issues, while Aβ42 promoted necrosis and specific inflammatory markers.
- Glucose deprivation (GD) primarily increased EC apoptosis and MMP2/ICAM1, whereas hypoxia more strongly affected necrosis and ZO-1 expression.
Conclusions:
- Hypoxia, low glucose, and amyloidosis synergistically induce cerebral EC dysfunction and death.
- Specific molecular pathways are identified through which these factors interact, offering potential therapeutic targets.
- Findings are crucial for understanding and treating vascular pathology in conditions like Alzheimer's Disease with cerebral amyloid angiopathy and hypoperfusion.
Background:
Disrupted brain hemodynamics and cerebrovascular damage resulting in cerebral hypoperfusion occur early within Alzheimer's Disease (AD) pathogenesis. Cerebral hypoperfusion is also an extremely common consequence of cardiovascular risk factors and diseases (CVRFs/CVDs), which usually manifest in midlife, when AD pathology initiates, and actively contribute to AD progression. Previously our lab has demonstrated that the vasculotropic Dutch mutant, AβQ22, and Aβ42 promote apoptosis, barrier permeability, and angiogenic impairments within cerebral endothelial cells (ECs) and prior research has indicated that hypoperfusion promotes analogous EC dysfunction. Aβ deposition occurs within a hypoperfused environment in AD, but whether exposure of cerebral ECs to Aβ under hypoperfusion conditions results in potentiated increases in cerebral EC dysfunction through activation of common molecular mechanisms remains unknown.
Method:
Human cerebral ECs were treated with Aβ40-Q22 or Aβ42, glucose deprivation (GD), or a combination of both, under normoxia or hypoxia conditions. Cell death mechanisms (apoptosis/necrosis), barrier dysfunction/permeability (TEER/BBB-regulating proteins/proinflammatory activation), and angiogenesis impairment (vessel branching/VEGF signaling) were evaluated.
Result:
Deprivation of glucose and/or oxygen potentiated Aβ-induced cerebral EC death, barrier instability, junction proteins dysregulation, inflammatory activation, and angiogenesis/wound healing failure. In particular, when in combination with hypoperfusion, AβQ22 exacerbated cerebral EC apoptosis, TEER/ZO1 decreases, ICAM1, IL6, and IL8 upregulation, monocyte migration, and wound healing impairments. Differentially, Aβ42, when in combination with hypoperfusion, more strongly potentiated increases in cerebral EC necrosis and MMP2, phosphorylated claudin-5, IFNγ, and IL12p70 expression. Additionally, this study identified that GD exerted stronger effects on promoting increases in cerebral EC caspase-3 activation, apoptosis, and MMP2/ICAM1 expression, while hypoxia demonstrated more robust effects on increasing necrosis, ZO1 expression, and pro-angiogenic protein expression.
Conclusion:
This study reveals specific mechanisms through which hypoxia, low glucose and amyloidosis mutually operate to produce brain EC dysfunction and death, highlighting new potential molecular targets against vascular pathology in comorbid AD/CAA and hypoperfusion conditions.
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