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Pericyte loss leads to circulatory failure and pleiotrophin depletion causing neuron loss

Angeliki M Nikolakopoulou1,2, Axel Montagne1,2, Kassandra Kisler1,2

  • 1Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, CA, USA.

Nature Neuroscience
|June 26, 2019
PubMed

Insights

Brain pericyte loss triggers rapid neurodegeneration by disrupting blood flow and reducing neurotrophic support. Restoring pleiotrophin (PTN) prevents neuron loss, highlighting pericytes

Area of Science:

  • Neuroscience
  • Vascular Biology
  • Cell Biology

Background:

  • Pericytes are crucial cells in the neurovasculature, situated between endothelial cells, astrocytes, and neurons.
  • Pericyte degeneration is observed in various neurological disorders, but their precise role in pathogenesis is unclear.
  • Understanding pericyte function is vital for addressing neurovascular dysfunction and neurological diseases.

Purpose of the Study:

  • To investigate the direct role of pericytes in neurological disorders.
  • To elucidate the mechanisms by which pericyte loss impacts neuronal survival and brain function.
  • To explore the therapeutic potential of pericyte-derived factors.

Main Methods:

  • Generation of an inducible pericyte-specific Cre mouse line crossed with iDTR mice for targeted pericyte ablation using diphtheria toxin.
  • Assessment of blood-brain barrier integrity, cerebral blood flow, and neuronal survival following pericyte depletion.
  • Intracerebroventricular infusion of pleiotrophin (PTN) to evaluate its neuroprotective effects.
  • Experimental silencing of pericyte-derived Ptn to determine its role in neuronal vulnerability.

Main Results:

  • Acute pericyte ablation led to rapid blood-brain barrier breakdown, severe cerebral blood flow reduction, and significant neuron loss.
  • Loss of pericyte-derived pleiotrophin (PTN), a key neurotrophic factor, was associated with neurodegeneration.
  • Intracerebroventricular PTN administration rescued neurons from loss in pericyte-ablated mice, despite persistent circulatory deficits.
  • Silencing Ptn in pericytes sensitized neurons to ischemic and excitotoxic injury.

Conclusions:

  • Pericyte loss initiates a rapid neurodegeneration cascade linked to circulatory collapse and diminished neurotrophic support.
  • Pericyte-derived PTN is essential for maintaining neuronal survival and protecting against injury.
  • These findings underscore the critical role of pericytes in maintaining brain homeostasis and suggest therapeutic avenues for neurological disorders involving neurovascular dysfunction.

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