Aβ1‐42 oligomers induce pericyte dysfunction via p75 Neurotrophin Receptor

Abstract

AbstractBackgroundAmyloid beta (Aβ) aggregates and tau tangles are hallmark pathologies of Alzheimer’s disease (AD). There is growing evidence that vascular dysfunction may contribute to the pathophysiology of AD. Pericyte injury and/or deterioration leading to blood‐brain barrier (BBB) breakdown occur in normal aging and are associated with cognitive impairment in AD patients. Furthermore, there is reduced cerebral blood flow in AD. Because vascular resistance occurs in capillaries, we hypothesize that Aβ1‐42 causes aberrant pericyte contraction and cell death via p75 neurotrophin receptor (p75NTR).Methodp75NTR levels were quantified via Western blotting in mouse vascular brain pericytes treated with either artificial cerebrospinal fluid (aCSF) as a control or 72 nM Aβ1‐42 oligomers for either 20 minutes or 24 hours. Furthermore, LIVE/DEAD assays were performed to quantify pericyte deterioration after exposure to 72 nM Aβ1‐42 for various time points. In mouse models, changes in red blood cell (RBC) flow due to pericyte contraction around capillaries were measured using intravital microscopy in the somatosensory cortex of anesthetized C57 mice and applying either topical aCSF or 72 nM Aβ1‐42.ResultAfter 20 minutes of aCSF or Aβ1‐42 treatment, there is a statistically significant increase in p75NTR levels (n = 3, p = 0.016, two‐tailed t‐test), while there is a statistically significant decrease by 43% in p75NTR levels after 24 hours (n = 6, p = 0.0028, two‐tailed t‐test). After 48 hours of aCSF or Aβ1‐42 treatment, 75.6% of the control pericytes were viable, whereas only 65.3% of the Aβ1‐42 treated pericytes were viable. Preliminary in vivo studies revealed that 72 nM Aβ1‐42 treatment stalled RBC flow.ConclusionPericytes were confirmed to express p75NTR. Aβ1‐42 treatment upregulates p75NTR expression after 20 minutes while downregulating its expression after 24 hours. This suggests that acute increases in p75NTR levels may mediate increased pericyte contraction and play a role in reduced cerebral blood flow during the progression of AD. Because the details of this mechanism are unknown, future in vivo studies will involve pericyte‐specific p75NTR knock‐out mice.