A control mechanism for intra-mural peri-arterial drainage via astrocytes: How neuronal activity could improve waste clearance from the brain

The mechanisms behind the clearance of soluble waste from deep within the parenchyma of the brain remain unclear. Experimental evidence reveals that one pathway for clearance of waste, termed intra-mural peri-arterial drainage (IPAD), is the rapid drainage of interstitial fluid along basement membranes (BM) of the smooth muscle cells of cerebral arteries; failure of IPAD is closely associated with the pathology of Alzheimer’s disease (AD), but its driving mechanism remains unclear. We have previously shown that arterial pulsations generated by the heart beat are not strong enough to drive IPAD. Here we present computational evidence for a mechanism for clearance of waste from the brain that is driven by functional hyperaemia, that is, the dilatation of cerebral arterioles as a consequence of increased nutrient demand from neurons. This mechanism is based on our model for the flow of fluid through the vascular BM. It accounts for clearance rates observed in mouse experiments, and aligns with pathological observations and recommendations to lower the individual risk of AD, such as mental and physical activity. Thus, our neurovascular hypothesis should act as the new working hypothesis for the driving force behind IPAD.

[1]  Alexandra K. Diem,et al.  Arterial Pulsations cannot Drive Intramural Periarterial Drainage: Significance for Aβ Drainage , 2017, Front. Neurosci..

[2]  Alexandra K. Diem,et al.  Peristalsis with Oscillating Flow Resistance: A Mechanism for Periarterial Clearance of Amyloid Beta from the Brain , 2015, Annals of Biomedical Engineering.

[3]  J. Levick.  Flow through interstitium and other fibrous matrices. , 1987, Quarterly journal of experimental physiology.

[4]  R O Weller,et al.  Solutes, but not cells, drain from the brain parenchyma along basement membranes of capillaries and arteries: significance for cerebral amyloid angiopathy and neuroimmunology , 2008, Neuropathology and applied neurobiology.

[5]  G. Carmignoto,et al.  Astrocyte control of synaptic transmission and neurovascular coupling. , 2006, Physiological reviews.

[6]  G. Em Karniadakis,et al.  A bidirectional model for communication in the neurovascular unit. , 2012, Journal of theoretical biology.

[7]  Anders Logg,et al.  The FEniCS Project Version 1.5 , 2015 .

[8]  T. Roose,et al.  A Model for Interstitial Drainage Through a Sliding Lymphatic Valve , 2015, Bulletin of mathematical biology.

[9]  Arne Møller,et al.  The capillary dysfunction hypothesis of Alzheimer's disease , 2013, Neurobiology of Aging.

[10]  G. E. Vates,et al.  A Paravascular Pathway Facilitates CSF Flow Through the Brain Parenchyma and the Clearance of Interstitial Solutes, Including Amyloid β , 2012, Science Translational Medicine.

[11]  Victoria M Perreau,et al.  Voluntary Exercise Decreases Amyloid Load in a Transgenic Model of Alzheimer's Disease , 2005, The Journal of Neuroscience.

[12]  Stephen M. Rao,et al.  Lifestyle and genetic contributions to cognitive decline and hippocampal structure and function in healthy aging. , 2012, Current Alzheimer research.

[13]  Stephen M. Rao,et al.  Physical activity reduces hippocampal atrophy in elders at genetic risk for Alzheimer's disease , 2014, Front. Aging Neurosci..

[14]  A. Ngai,et al.  Correlation of intrinsic optical signal, cerebral blood flow, and evoked potentials during activation of rat somatosensory cortex. , 2008, Journal of neurosurgery.

[15]  C. Hillman,et al.  The influence of exercise on cognitive abilities. , 2013, Comprehensive Physiology.

[16]  J. Schneider,et al.  Cognitive activity and incident AD in a population-based sample of older persons , 2002, Neurology.

[17]  R. Weller,et al.  Microvasculature changes and cerebral amyloid angiopathy in Alzheimer’s disease and their potential impact on therapy , 2009, Acta Neuropathologica.

[18]  B. Zlokovic,et al.  Neurovascular dysfunction and neurodegeneration in dementia and Alzheimer's disease. , 2016, Biochimica et biophysica acta.

[19]  Reinhard Schliebs,et al.  Perivascular drainage of solutes is impaired in the ageing mouse brain and in the presence of cerebral amyloid angiopathy , 2011, Acta Neuropathologica.

[20]  B. Winblad,et al.  An active and socially integrated lifestyle in late life might protect against dementia , 2004, The Lancet Neurology.

[21]  Altered neurovascular coupling as measured by optical imaging: a biomarker for Alzheimer’s disease , 2017, Scientific Reports.

[22]  R. Thorne,et al.  Molecular characterization of perivascular drainage pathways in the murine brain , 2017, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[23]  S. Hladky,et al.  Mechanisms of fluid movement into, through and out of the brain: evaluation of the evidence , 2014, Fluids and Barriers of the CNS.

[24]  Roxana O. Carare,et al.  Convective influx/glymphatic system: tracers injected into the CSF enter and leave the brain along separate periarterial basement membrane pathways , 2018, Acta Neuropathologica.

[25]  R. Carare,et al.  Failure of Perivascular Drainage of β‐amyloid in Cerebral Amyloid Angiopathy , 2014, Brain pathology.

[26]  D. de Zélicourt,et al.  How astrocyte networks may contribute to cerebral metabolite clearance , 2015, Scientific Reports.

[27]  Seth Love,et al.  Small vessels, dementia and chronic diseases - molecular mechanisms and pathophysiology. , 2016, Clinical science.

[28]  V. Perry,et al.  Mechanisms to explain the reverse perivascular transport of solutes out of the brain. , 2006, Journal of theoretical biology.

[29]  Brian J. Bacskai,et al.  Interstitial fluid drainage is impaired in ischemic stroke and Alzheimer’s disease mouse models , 2013, Acta Neuropathologica.

[30]  R. Carare,et al.  The Cerebrovascular Basement Membrane: Role in the Clearance of β-amyloid and Cerebral Amyloid Angiopathy , 2014, Front. Aging Neurosci..

[31]  Y. Stern,et al.  Influence of leisure activity on the incidence of Alzheimer’s Disease , 2001, Neurology.

[32]  Tim David,et al.  Models of neurovascular coupling via potassium and EET signalling. , 2011, Journal of theoretical biology.

[33]  S. Waxman,et al.  Specialization of astrocytic membrane at glia limitans in rat optic nerve: Freeze-fracture observations , 1985, Neuroscience Letters.

[35]  R. Carare,et al.  The meninges as barriers and facilitators for the movement of fluid, cells and pathogens related to the rodent and human CNS , 2018, Acta Neuropathologica.

[36]  B. Zlokovic.  The Blood-Brain Barrier in Health and Chronic Neurodegenerative Disorders , 2008, Neuron.