• Medientyp: E-Artikel
  • Titel: Neurovascular Uncoupling in TgF344‐AD Rats is Associated with Reduced Cerebral Capillary Endothelial Kir2.1 Expression
  • Beteiligte: Fang, Xing; Border, Jane J.; Crumpler, Reece F.; Strong, Luke B.; Roman, Richard J.; Fan, Fan
  • Erschienen: Wiley, 2022
  • Erschienen in: Alzheimer's & Dementia
  • Umfang:
  • Sprache: Englisch
  • DOI: 10.1002/alz.066929
  • ISSN: 1552-5260; 1552-5279
  • Schlagwörter: Psychiatry and Mental health ; Cellular and Molecular Neuroscience ; Geriatrics and Gerontology ; Neurology (clinical) ; Developmental Neuroscience ; Health Policy ; Epidemiology
  • Zusammenfassung: <jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>Alzheimer’s disease (AD) is an emerging global health care crisis. Although reduced cerebral blood flow (CBF) is an early and persistent symptom in developing cognitive deficits, the underlying molecular and cellular mechanisms remain unclear. Recent studies suggested that restoration of capillary endothelial cells (ECs) inward‐rectifier potassium channels (Kir2.1) currents reversed cerebral hypoperfusion and enhanced neurovascular coupling in AD mice. The present study aims to investigate whether capillary ECs Kir2.1 expression is reduced in TgF344‐AD rats and whether it contributes to neurovascular uncoupling and cognitive deficits.</jats:p></jats:sec><jats:sec><jats:title>Method</jats:title><jats:p>Three to six months old TgF‐344 AD rats expressing mutant human APP and PS1 and their age‐matched wildtype (WT) rats were studied. An eight‐arm water maze was used to test spatial learning and short and long‐term memory. Brain perfusion was mapped with a laser speckle imaging system. Whisker stimulation‐induced functional hyperemia was measured using laser Doppler flowmetry <jats:italic>in vivo</jats:italic>. Brain Kir2.1 expression was compared using western blot. Cerebral parenchymal arterioles (PAs) with attached capillaries were freshly isolated from AD and WT rats and mounted in a pressure myography. PAs response to capillaries focally injected KCL (10 mM) and Kir2.1 inhibitor (ML133) was compared.</jats:p></jats:sec><jats:sec><jats:title>Result</jats:title><jats:p>AD rats exhibited learning and memory dysfunction at 6‐month of age compared with WT controls. However, cerebral hypoperfusion was observed in AD rats starting from 4‐month of age. Similarly, impaired functional hyperemia in AD rats started at 4‐month of age, which was exacerbated in 6‐month old AD rats. The expression of Kir2.1 in 6‐month AD brain tissue was significantly lower than in WT rats. AD PAs displayed less vasodilation (110.96 ± 3.92 % vs. 122.93 ± 1.97 %) and vasoconstriction (92.16 ± 3.47 % vs. 78.04 ± 2.96 %) in response to capillary administered KCL and ML133, respectively, compared to WT vessels.</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>Reduced brain hypoperfusion precedes cognitive impairment in AD rats, associated with attenuated capillary EC Kir2.1 expression and neurovascular uncoupling.</jats:p></jats:sec>
  • Beschreibung: <jats:title>Abstract</jats:title><jats:sec><jats:title>Background</jats:title><jats:p>Alzheimer’s disease (AD) is an emerging global health care crisis. Although reduced cerebral blood flow (CBF) is an early and persistent symptom in developing cognitive deficits, the underlying molecular and cellular mechanisms remain unclear. Recent studies suggested that restoration of capillary endothelial cells (ECs) inward‐rectifier potassium channels (Kir2.1) currents reversed cerebral hypoperfusion and enhanced neurovascular coupling in AD mice. The present study aims to investigate whether capillary ECs Kir2.1 expression is reduced in TgF344‐AD rats and whether it contributes to neurovascular uncoupling and cognitive deficits.</jats:p></jats:sec><jats:sec><jats:title>Method</jats:title><jats:p>Three to six months old TgF‐344 AD rats expressing mutant human APP and PS1 and their age‐matched wildtype (WT) rats were studied. An eight‐arm water maze was used to test spatial learning and short and long‐term memory. Brain perfusion was mapped with a laser speckle imaging system. Whisker stimulation‐induced functional hyperemia was measured using laser Doppler flowmetry <jats:italic>in vivo</jats:italic>. Brain Kir2.1 expression was compared using western blot. Cerebral parenchymal arterioles (PAs) with attached capillaries were freshly isolated from AD and WT rats and mounted in a pressure myography. PAs response to capillaries focally injected KCL (10 mM) and Kir2.1 inhibitor (ML133) was compared.</jats:p></jats:sec><jats:sec><jats:title>Result</jats:title><jats:p>AD rats exhibited learning and memory dysfunction at 6‐month of age compared with WT controls. However, cerebral hypoperfusion was observed in AD rats starting from 4‐month of age. Similarly, impaired functional hyperemia in AD rats started at 4‐month of age, which was exacerbated in 6‐month old AD rats. The expression of Kir2.1 in 6‐month AD brain tissue was significantly lower than in WT rats. AD PAs displayed less vasodilation (110.96 ± 3.92 % vs. 122.93 ± 1.97 %) and vasoconstriction (92.16 ± 3.47 % vs. 78.04 ± 2.96 %) in response to capillary administered KCL and ML133, respectively, compared to WT vessels.</jats:p></jats:sec><jats:sec><jats:title>Conclusion</jats:title><jats:p>Reduced brain hypoperfusion precedes cognitive impairment in AD rats, associated with attenuated capillary EC Kir2.1 expression and neurovascular uncoupling.</jats:p></jats:sec>
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