Characterisation of PDGF-BB:PDGFRβ signalling pathways in human brain pericytes: evidence of disruption in Alzheimer’s disease

Smyth, Leon; Highet, Blake; Jansson, Deidre; Wu, Jane Y.; Rustenhoven, Justin; Aalderink, Miranda; Tan, Adelie Y. S.; Li, Susan; Johnson, Rebecca; Coppieters, Natacha; Handley, Renee; Narayan, Pritika; Singh‐Bains, Malvindar K.; Schweder, Patrick; Turner, Clinton; Mee, Edward; Heppner, Peter; Correia, Jason; Park, Thomas I-H; Curtis, Maurice A.; Faull, Richard L.M.; Dragunow, Michael

doi:10.1038/s42003-022-03180-8

Cited by 43 publications

(23 citation statements)

References 71 publications

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“…Augmenting PDGF-B/PDGFRβ activity in adulthood may therefore be a strategy to increase pericyte coverage and improve capillary homeostasis. In vitro, administration of PDGF-BB leads to proliferation of human brain pericytes and protection from apoptosis 52 . Intravenous treatment with PDGF-BB peptide was sufficient to promote pericyte coverage and restore capillary tone and flow rate in a model of epilepsy involving mural cell loss 53 .…”

Section: Discussionmentioning

confidence: 99%

Pericyte remodeling is deficient in the aged brain and contributes to impaired capillary flow and structure

et al. 2022

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Deterioration of brain capillary flow and architecture is a hallmark of aging and dementia. It remains unclear how loss of brain pericytes in these conditions contributes to capillary dysfunction. Here, we conduct cause-and-effect studies by optically ablating pericytes in adult and aged mice in vivo. Focal pericyte loss induces capillary dilation without blood-brain barrier disruption. These abnormal dilations are exacerbated in the aged brain, and result in increased flow heterogeneity in capillary networks. A subset of affected capillaries experience reduced perfusion due to flow steal. Some capillaries stall in flow and regress, leading to loss of capillary connectivity. Remodeling of neighboring pericytes restores endothelial coverage and vascular tone within days. Pericyte remodeling is slower in the aged brain, resulting in regions of persistent capillary dilation. These findings link pericyte loss to disruption of capillary flow and structure. They also identify pericyte remodeling as a therapeutic target to preserve capillary flow dynamics.

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Section: Discussionmentioning

confidence: 99%

Pericyte remodeling is deficient in the aged brain and contributes to impaired capillary flow and structure

et al. 2022

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“…In vitro, administration of PDGF-BB leads to proliferation of human brain pericytes and protection from apoptosis. 52 Intravenous treatment with PDGF-BB peptide was sufficient to promote pericyte coverage and restore capillary tone and flow rate in a model of epilepsy involving mural cell loss. 53 Interestingly, the immunomodulatory drug, thalidomide, can increase expression of PDGF-BB from endothelial cells, promoting pericyte coverage and reducing bleeding in models exhibiting vascular pathology in the CNS 54 and peripheral tissues.…”

Section: Discussionmentioning

confidence: 99%

Pericyte remodeling is deficient in the aged brain and contributes to impaired capillary flow and structure

Berthiaume

Schmid

Stamenković

et al. 2022

Preprint

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Deterioration of brain capillary flow and architecture is a hallmark of aging and dementia. It remains unclear how loss of brain pericytes in these conditions contributes to capillary dysfunction. We conducted cause-and-effect studies by optically ablating pericytes in adult and aged mice in vivo. Focal pericyte loss induced capillary dilation without blood-brain barrier disruption. These abnormal dilations were exacerbated in the aged brain, and resulted in increased flow heterogeneity in capillary networks. A subset of affected capillaries reduced in perfusion due to flow steal. Some capillaries stalled in flow and regressed, leading to loss of capillary connectivity. Remodeling of neighboring pericytes restored endothelial coverage and vascular tone within days. Pericyte remodeling was slower in the aged brain, resulting in regions of persistent capillary dilation. These findings link pericyte loss to disruption of capillary flow and structure. They also identify pericyte remodeling as a therapeutic target to preserve capillary flow dynamics.

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“…A potential therapeutic approach would be to apply blockers of pericyte voltage-gated Ca 2+ channels. Endothelial cells release PDGF-BB which binds to PDGFRβ on pericytes, enhancing their proliferation and recruiting them to the endothelial tube [ 186 ]. Icv administration of exogenous PDGF-BB has entered human clinical trials (NCT02408562) and appears to be well-tolerated and safe.…”

Section: Inflammation and Admentioning

confidence: 99%

Symptomatic and Disease-Modifying Therapy Pipeline for Alzheimer’s Disease: Towards a Personalized Polypharmacology Patient-Centered Approach

Morató

Pytel

Jofresa

et al. 2022

IJMS

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Since 1906, when Dr. Alois Alzheimer first described in a patient “a peculiar severe disease process of the cerebral cortex”, people suffering from this pathology have been waiting for a breakthrough therapy. Alzheimer’s disease (AD) is an irreversible, progressive neurodegenerative brain disorder and the most common form of dementia in the elderly with a long presymptomatic phase. Worldwide, approximately 50 million people are living with dementia, with AD comprising 60–70% of cases. Pathologically, AD is characterized by the deposition of amyloid β-peptide (Aβ) in the neuropil (neuritic plaques) and blood vessels (amyloid angiopathy), and by the accumulation of hyperphosphorylated tau in neurons (neurofibrillary tangles) in the brain, with associated loss of synapses and neurons, together with glial activation, and neuroinflammation, resulting in cognitive deficits and eventually dementia. The current competitive landscape in AD consists of symptomatic treatments, of which there are currently six approved medications: three AChEIs (donepezil, rivastigmine, and galantamine), one NMDA-R antagonist (memantine), one combination therapy (memantine/donepezil), and GV-971 (sodium oligomannate, a mixture of oligosaccharides derived from algae) only approved in China. Improvements to the approved therapies, such as easier routes of administration and reduced dosing frequencies, along with the developments of new strategies and combined treatments are expected to occur within the next decade and will positively impact the way the disease is managed. Recently, Aducanumab, the first disease-modifying therapy (DMT) has been approved for AD, and several DMTs are in advanced stages of clinical development or regulatory review. Small molecules, mAbs, or multimodal strategies showing promise in animal studies have not confirmed that promise in the clinic (where small to moderate changes in clinical efficacy have been observed), and therefore, there is a significant unmet need for a better understanding of the AD pathogenesis and the exploration of alternative etiologies and therapeutic effective disease-modifying therapies strategies for AD. Therefore, a critical review of the disease-modifying therapy pipeline for Alzheimer’s disease is needed.

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Characterisation of PDGF-BB:PDGFRβ signalling pathways in human brain pericytes: evidence of disruption in Alzheimer’s disease

Cited by 43 publications

References 71 publications

Pericyte remodeling is deficient in the aged brain and contributes to impaired capillary flow and structure

Pericyte remodeling is deficient in the aged brain and contributes to impaired capillary flow and structure

Pericyte remodeling is deficient in the aged brain and contributes to impaired capillary flow and structure

Symptomatic and Disease-Modifying Therapy Pipeline for Alzheimer’s Disease: Towards a Personalized Polypharmacology Patient-Centered Approach

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