Differentially Severe Cognitive Effects of Compromised Cerebral Blood Flow in Aged Mice: Association with Myelin Degradation and Microglia Activation

Bilateral common carotid artery stenosis (BCAS) models the effects of compromised cerebral blood flow on brain structure and function in mice. We compared the effects of BCAS in aged (21 month) and young adult (3 month) female mice, anticipating a differentially more severe effect in the older mice. Four weeks after surgery there was a significant age by time by treatment interaction on the radial-arm water maze (RAWM; p = 0.014): on the first day of the test, latencies of old mice were longer compared to the latencies of young adult mice, independent of BCAS. However, on the second day of the test, latencies of old BCAS mice were significantly longer than old control mice (p = 0.049), while latencies of old controls were similar to those of the young adult mice, indicating more severe impairment of hippocampal dependent learning and working memory by BCAS in the older mice. Fluorescence staining of myelin basic protein (MBP) showed that old age and BCAS both induced a significant decrease in fluorescence intensity. Evaluation of the number oligodendrocyte precursor cells demonstrated augmented myelin replacement in old BCAS mice (p < 0.05) compared with young adult BCAS and old control mice. While microglia morphology was assessed as normal in young adult control and young adult BCAS mice, microglia of old BCAS mice exhibited striking activation in the area of degraded myelin compared to young adult BCAS (p < 0.01) and old control mice (p < 0.05). These findings show a differentially more severe effect of cerebral hypoperfusion on cognitive function, myelin integrity and inflammatory processes in aged mice. Hypoperfusion may exacerbate degradation initiated by aging, which may induce more severe neuronal and cognitive phenotypes.

[1]  M. Ihara,et al.  Lessons from a Mouse Model Characterizing Features of Vascular Cognitive Impairment with White Matter Changes , 2011, Journal of aging research.

[2]  E. Wood,et al.  Gliovascular Disruption and Cognitive Deficits in a Mouse Model with Features of Small Vessel Disease , 2015, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[3]  V. Arango,et al.  Molecular aging in human prefrontal cortex is selective and continuous throughout adult life , 2005, Biological Psychiatry.

[4]  I. Deary,et al.  Selective white matter pathology induces a specific impairment in spatial working memory , 2011, Neurobiology of Aging.

[5]  E. Richfield,et al.  Age‐related irreversible progressive nigrostriatal dopaminergic neurotoxicity in the paraquat and maneb model of the Parkinson's disease phenotype , 2003, The European journal of neuroscience.

[6]  C. Cotman,et al.  Extensive innate immune gene activation accompanies brain aging, increasing vulnerability to cognitive decline and neurodegeneration: a microarray study , 2012, Journal of Neuroinflammation.

[7]  G. Breese,et al.  Stress and Withdrawal from Chronic Ethanol Induce Selective Changes in Neuroimmune mRNAs in Differing Brain Sites , 2016, Brain sciences.

[8]  V. Perry,et al.  Systemic Inflammation Induces Acute Behavioral and Cognitive Changes and Accelerates Neurodegenerative Disease , 2009, Biological Psychiatry.

[9]  J. O'Brien,et al.  White Matter Lesions in an Unselected Cohort of the Elderly: Molecular Pathology Suggests Origin From Chronic Hypoperfusion Injury , 2006, Stroke.

[10]  C. Kessler,et al.  Accelerated infarct development, cytogenesis and apoptosis following transient cerebral ischemia in aged rats , 2007, Acta Neuropathologica.

[11]  J. Fowler,et al.  Restoration of Oligodendrocyte Pools in a Mouse Model of Chronic Cerebral Hypoperfusion , 2014, PloS one.

[12]  Y. Ke,et al.  CX3CL1/CX3CR1-Mediated Microglia Activation Plays a Detrimental Role in Ischemic Mice Brain via p38MAPK/PKC Pathway , 2015, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[13]  M. Sabbagh,et al.  Intracranial atherosclerosis as a contributing factor to Alzheimer’s disease dementia , 2009, Alzheimer's & Dementia.

[14]  I. Cuthill,et al.  Reporting : The ARRIVE Guidelines for Reporting Animal Research , 2010 .

[15]  J. Ferro,et al.  White matter changes and late-life depressive symptoms , 2007, British Journal of Psychiatry.

[16]  N. Terrando,et al.  Prolonged Neuroinflammation after Lipopolysaccharide Exposure in Aged Rats , 2014, PloS one.

[17]  S. Itohara,et al.  Matrix Metalloproteinase-2 Plays a Critical Role in the Pathogenesis of White Matter Lesions After Chronic Cerebral Hypoperfusion in Rodents , 2006, Stroke.

[18]  D. Diamond,et al.  Two-day radial-arm water maze learning and memory task; robust resolution of amyloid-related memory deficits in transgenic mice , 2006, Nature Protocols.

[19]  David A. Bennett,et al.  Relation of Cerebral Vessel Disease to Alzheimer’s Disease Dementia and Cognitive Function in Older Persons: A Cross-sectional Study , 2016, The Lancet Neurology.

[20]  X. Hou,et al.  Ecto-5′-nucleotidase (CD73) is involved in chronic cerebral hypoperfusion-induced white matter lesions and cognitive impairment by regulating glial cell activation and pro-inflammatory cytokines , 2015, Neuroscience.

[21]  D. Connor,et al.  Circle of Willis atherosclerosis: association with Alzheimer’s disease, neuritic plaques and neurofibrillary tangles , 2006, Acta Neuropathologica.

[22]  A. Popa-Wagner,et al.  Preclinical models of stroke in aged animals with or without comorbidities: role of neuroinflammation , 2013, Biogerontology.

[23]  M. Ihara,et al.  White Matter Lesions and Glial Activation in a Novel Mouse Model of Chronic Cerebral Hypoperfusion , 2004, Stroke.

[24]  F. Calon,et al.  Old age potentiates cold-induced tau phosphorylation: linking thermoregulatory deficit with Alzheimer's disease , 2017, Neurobiology of Aging.

[25]  A. Popa-Wagner,et al.  Perfusion deficits, inflammation and aging precipitate depressive behaviour , 2014, Biogerontology.

[26]  H. Fukuyama,et al.  A Mouse Model Characterizing Features of Vascular Dementia With Hippocampal Atrophy , 2010, Stroke.

[27]  D. Jolley,et al.  Cost benefits of a medically supervised day treatment program for patients with Alzheimer's disease and other forms of dementia , 1989 .

[28]  H. D. Vanguilder,et al.  Concurrent hippocampal induction of MHC II pathway components and glial activation with advanced aging is not correlated with cognitive impairment , 2011, Journal of Neuroinflammation.

[29]  A. Brun,et al.  Pathology and pathophysiology of cerebrovascular dementia: pure subgroups of obstructive and hypoperfusive etiology. , 1994, Dementia.

[30]  Erratum to: NT-020 treatment reduces inflammation and augments Nrf-2 and Wnt signaling in aged rats , 2015, Journal of Neuroinflammation.

[31]  J. Teeling,et al.  Age related changes in microglial phenotype vary between CNS regions: Grey versus white matter differences , 2012, Brain, Behavior, and Immunity.

[32]  Kristine Yaffe,et al.  Trajectories of Depressive Symptoms in Older Adults and Risk of Dementia. , 2016, JAMA psychiatry.

[33]  E. Sibille,et al.  The age-by-disease interaction hypothesis of late-life depression. , 2012, The American journal of geriatric psychiatry : official journal of the American Association for Geriatric Psychiatry.

[34]  S. Maier,et al.  A Role for Proinflammatory Cytokines and Fractalkine in Analgesia, Tolerance, and Subsequent Pain Facilitation Induced by Chronic Intrathecal Morphine , 2004, The Journal of Neuroscience.

[35]  Tao Zhang,et al.  Impairment of Cognitive Function and Synaptic Plasticity Associated with Alteration of Information Flow in Theta and Gamma Oscillations in Melamine-Treated Rats , 2013, PloS one.

[36]  Jordan Muraskin,et al.  Structural neuroimaging in Alzheimer's disease: do white matter hyperintensities matter? , 2009, Dialogues in clinical neuroscience.

[37]  Bu-Yeo Kim,et al.  Cardiotonic pill attenuates white matter and hippocampal damage via inhibiting microglial activation and downregulating ERK and p38 MAPK signaling in chronic cerebral hypoperfused rat , 2013, BMC Complementary and Alternative Medicine.

[38]  Sang Won Seo,et al.  Hippocampal volume and shape in pure subcortical vascular dementia , 2015, Neurobiology of Aging.

[39]  S. Maier,et al.  Glial activation and pathological pain , 2004, Neurochemistry International.

[40]  J. Vaupel.  Biodemography of human ageing , 2010, Nature.

[41]  Florian J. Gerich,et al.  Astroglial NF-kB contributes to white matter damage and cognitive impairment in a mouse model of vascular dementia , 2016, Acta neuropathologica communications.

[42]  S. Maier,et al.  Aging sensitizes rapidly isolated hippocampal microglia to LPS ex vivo , 2010, Journal of Neuroimmunology.

[43]  R. Waddington,et al.  Clonal Heterogeneity in the Neuronal and Glial Differentiation of Dental Pulp Stem/Progenitor Cells , 2016, Stem cells international.

[44]  C. Kessler,et al.  The response of the aged brain to stroke: too much, too soon? , 2007, Current neurovascular research.

[45]  R. Kalaria.  Neuropathological diagnosis of vascular cognitive impairment and vascular dementia with implications for Alzheimer’s disease , 2016, Acta Neuropathologica.

[46]  I. Ionov,et al.  Histamine- and haloperidol-induced catalepsy in aged mice: differential responsiveness to l-DOPA , 2012, Psychopharmacology.

[47]  G. Martin,et al.  The genetics of aging. , 2003, Annual review of genomics and human genetics.

[48]  A. Lee,et al.  Vascular Dementia , 2011, Chonnam medical journal.

[49]  R. Kalaria,et al.  Selective Impairment of Working Memory in a Mouse Model of Chronic Cerebral Hypoperfusion , 2007, Stroke.