{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,30]],"date-time":"2026-09-30T21:29:23Z","timestamp":1790803763435,"version":"4.1.0"},"reference-count":39,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2020,5,5]],"date-time":"2020-05-05T00:00:00Z","timestamp":1588636800000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2020,5,5]],"date-time":"2020-05-05T00:00:00Z","timestamp":1588636800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Sci Rep"],"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Early impairments to neurovascular coupling have been proposed to be a key pathogenic factor in the onset and progression of Alzheimer\u2019s disease (AD). Studies have shown impaired neurovascular function in several mouse models of AD, including the J20-hAPP mouse. In this study, we aimed to investigate early neurovascular changes using wild-type (WT) controls and J20-hAPP mice at 6 months of age, by measuring cerebral haemodynamics and neural activity to physiological sensory stimulations. A thinned cranial window was prepared to allow access to cortical vasculature and imaged using 2D-optical imaging spectroscopy (2D-OIS). After chronic imaging sessions where the skull was intact, a terminal acute imaging session was performed where an electrode was inserted into the brain to record simultaneous neural activity. We found that cerebral haemodynamic changes were significantly enhanced in J20-hAPP mice compared with controls in response to physiological stimulations, potentially due to the significantly higher neural activity (hyperexcitability) seen in the J20-hAPP mice. Thus, neurovascular coupling remained preserved under a chronic imaging preparation. Further, under hyperoxia, the baseline blood volume and saturation of all vascular compartments in the brains of J20-hAPP mice were substantially enhanced compared to WT controls, but this effect disappeared under normoxic conditions. This study highlights novel findings not previously seen in the J20-hAPP mouse model, and may point towards a potential therapeutic strategy.<\/jats:p>","DOI":"10.1038\/s41598-020-64334-4","type":"journal-article","created":{"date-parts":[[2020,5,5]],"date-time":"2020-05-05T06:02:48Z","timestamp":1588658568000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Enhanced Cerebral Blood Volume under Normobaric Hyperoxia in the J20-hAPP Mouse Model of Alzheimer\u2019s Disease"],"prefix":"10.1038","volume":"10","author":[{"given":"Osman","family":"Shabir","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Sharp","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Monica A.","family":"Rebollar","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Luke","family":"Boorman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clare","family":"Howarth","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephen B.","family":"Wharton","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sheila E.","family":"Francis","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jason","family":"Berwick","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2020,5,5]]},"reference":[{"key":"64334_CR1","doi-asserted-by":"publisher","unstructured":"Wright, A. L. et al. Neuroinflammation and Neuronal Loss Precede A\u03b2 Plaque Deposition in the hAPP-J20 Mouse Model of Alzheimer\u2019s Disease. PLoS One, https:\/\/doi.org\/10.1371\/journal.pone.0059586 (2013).","DOI":"10.1371\/journal.pone.0059586"},{"key":"64334_CR2","doi-asserted-by":"publisher","unstructured":"Ameen-Ali, K. E. et al. Review: Neuropathology and behavioural features of transgenic murine models of Alzheimer\u2019s disease. Neuropathology and Applied Neurobiology, https:\/\/doi.org\/10.1111\/nan.12440 (2017).","DOI":"10.1111\/nan.12440"},{"key":"64334_CR3","doi-asserted-by":"publisher","unstructured":"Webster, S. J., Bachstetter, A. D., Nelson, P. T., Schmitt, F. A. & Van Eldik, L. J. Using mice to model Alzheimer\u2019s dementia: An overview of the clinical disease and the preclinical behavioral changes in 10 mouse models. Front. Genet., https:\/\/doi.org\/10.3389\/fgene.2014.00088 (2014).","DOI":"10.3389\/fgene.2014.00088"},{"key":"64334_CR4","doi-asserted-by":"publisher","unstructured":"Sengupta, U., Nilson, A. N. & Kayed, R. The Role of Amyloid-\u03b2 Oligomers in Toxicity, Propagation, and Immunotherapy. EbioMedicine, https:\/\/doi.org\/10.1016\/j.ebiom.2016.03.035 (2016).","DOI":"10.1016\/j.ebiom.2016.03.035"},{"key":"64334_CR5","doi-asserted-by":"publisher","unstructured":"Mucke, L. et al. High-level neuronal expression of A\u03b2(1-42) in wild-type human amyloid protein precursor transgenic mice: Synaptotoxicity without plaque formation. J. Neurosci., https:\/\/doi.org\/10.1523\/jneurosci.20-11-04050.2000 (2000).","DOI":"10.1523\/jneurosci.20-11-04050.2000"},{"key":"64334_CR6","doi-asserted-by":"publisher","unstructured":"Ameen-Ali, K. E. et al. The Time Course of Recognition Memory Impairment and Glial Pathology in the hAPP-J20 Mouse Model of Alzheimer\u2019s Disease. J. Alzheimer\u2019s Dis., https:\/\/doi.org\/10.3233\/JAD-181238 (2019).","DOI":"10.3233\/JAD-181238"},{"key":"64334_CR7","doi-asserted-by":"publisher","unstructured":"Zlokovic, B. V. Neurovascular mechanisms of Alzheimer\u2019s neurodegeneration. Trends in Neurosciences, https:\/\/doi.org\/10.1016\/j.tins.2005.02.001 (2005).","DOI":"10.1016\/j.tins.2005.02.001"},{"key":"64334_CR8","doi-asserted-by":"publisher","unstructured":"Zlokovic, B. V. Neurovascular pathways to neurodegeneration in Alzheimer\u2019s disease and other disorders. Nature Reviews Neuroscience, https:\/\/doi.org\/10.1038\/nrn3114 (2011).","DOI":"10.1038\/nrn3114"},{"key":"64334_CR9","doi-asserted-by":"publisher","unstructured":"Iturria-Medina, Y. et al. Early role of vascular dysregulation on late-onset Alzheimer\u2019s disease based on multifactorial data-driven analysis. Nat. Commun., https:\/\/doi.org\/10.1038\/ncomms11934 (2016).","DOI":"10.1038\/ncomms11934"},{"key":"64334_CR10","doi-asserted-by":"crossref","unstructured":"Sharp, P. S. et al. Neurovascular coupling preserved in a chronic mouse model of Alzheimer\u2019s disease: Methodology is critical. J. Cereb. Blood Flow Metab. In Press, (2019).","DOI":"10.1177\/0271678X19890830"},{"key":"64334_CR11","doi-asserted-by":"publisher","unstructured":"Lacoste, B., Tong, X. K., Lahjouji, K., Couture, R. & Hamel, E. Cognitive and cerebrovascular improvements following kinin B1 receptor blockade in Alzheimer\u2019s disease mice. J. Neuroinflammation, https:\/\/doi.org\/10.1186\/1742-2094-10-57 (2013).","DOI":"10.1186\/1742-2094-10-57"},{"key":"64334_CR12","doi-asserted-by":"publisher","unstructured":"Ongali, B. et al. Angiotensin II type 1 receptor blocker losartan prevents and rescues cerebrovascular, neuropathological and cognitive deficits in an Alzheimer\u2019s disease model. Neurobiol. Dis., https:\/\/doi.org\/10.1016\/j.nbd.2014.04.018 (2014).","DOI":"10.1016\/j.nbd.2014.04.018"},{"key":"64334_CR13","doi-asserted-by":"publisher","unstructured":"Royea, J., Zhang, L., Tong, X. K. & Hamel, E. Angiotensin IV receptors mediate the cognitive and cerebrovascular benefits of losartan in a mouse model of Alzheimer\u2019s disease. J. Neurosci., https:\/\/doi.org\/10.1523\/JNEUROSCI.0329-17.2017 (2017).","DOI":"10.1523\/JNEUROSCI.0329-17.2017"},{"key":"64334_CR14","doi-asserted-by":"publisher","unstructured":"Kim, J. & Jeong, Y. Augmentation of sensory-evoked hemodynamic response in an early alzheimer\u2019s disease mouse model. J. Alzheimer\u2019s Dis., https:\/\/doi.org\/10.3233\/JAD-121900 (2013).","DOI":"10.3233\/JAD-121900"},{"key":"64334_CR15","doi-asserted-by":"publisher","unstructured":"Nedergaard, M. Garbage truck of t\u00a0he brain. Science, https:\/\/doi.org\/10.1126\/science.1240514 (2013).","DOI":"10.1126\/science.1240514"},{"key":"64334_CR16","doi-asserted-by":"publisher","unstructured":"Aldea, R., Weller, R. O., Wilcock, D. M., Carare, R. O. & Richardson, G. Cerebrovas\u00a0cular smooth muscle cells as the drivers of intramural periarterial drainage of the brain. Front. Aging Neurosci., https:\/\/doi.org\/10.3389\/fnagi.2019.00001 (2019).","DOI":"10.3389\/fnagi.2019.00001"},{"key":"64334_CR17","doi-asserted-by":"publisher","unstructured":"Shapira, R., Solomon, B., Efrati, S., Frenkel, D. & Ashery, U. Hyperbaric oxygen therapy ameliorates pathophysiology of 3xTg-AD mouse model by attenuating neuroinflammation. Neurobiol. Aging, https:\/\/doi.org\/10.1016\/j.neurobiolaging.2017.10.007 (2018).","DOI":"10.1016\/j.neurobiolaging.2017.10.007"},{"key":"64334_CR18","doi-asserted-by":"publisher","unstructured":"Palop, J. J. & Mucke, L. Network abnormalities and interneuron dysfunction in Alzheimer disease. Nature Reviews Neuroscience, https:\/\/doi.org\/10.1038\/nrn.2016.141 (2016).","DOI":"10.1038\/nrn.2016.141"},{"key":"64334_CR19","doi-asserted-by":"publisher","unstructured":"Ping, Y. et al. Linking A\u03b242-Induced Hyperexcitability to Neurodegeneration, Learning and Motor Deficits, and a Shorter Lifespan in an Alzheimer\u2019s Model. PLoS Genet., https:\/\/doi.org\/10.1371\/journal.pgen.1005025. (2015)","DOI":"10.1371\/journal.pgen.1005025"},{"key":"64334_CR20","doi-asserted-by":"publisher","unstructured":"Minkeviciene, R. et al. Amyloid \u03b2-induced neuronal hyperexcitability triggers progressive epilepsy. J. Neurosci., https:\/\/doi.org\/10.1523\/JNEUROSCI.5215-08.2009 (2009).","DOI":"10.1523\/JNEUROSCI.5215-08.2009"},{"key":"64334_CR21","doi-asserted-by":"publisher","unstructured":"Palop, J. J. & Mucke, L. Amyloid-\u0392-induced neuronal dysfunction in Alzheimer\u2019s disease: From synapses toward neural networks. Nature Neuroscience, https:\/\/doi.org\/10.1038\/nn.2583 (2010).","DOI":"10.1038\/nn.2583"},{"key":"64334_CR22","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1206171109","author":"MA Busche","year":"2012","unstructured":"Busche, M. A. et al. Critical role of soluble amyloid-\u03b2 for early hippocampal hyperactivity in a mouse model of Alzheimer\u2019s disease. Proc. Natl. Acad. Sci. USA https:\/\/doi.org\/10.1073\/pnas.1206171109 (2012).","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"64334_CR23","doi-asserted-by":"publisher","unstructured":"Palop, J. J. et al. Aberrant Excitatory Neuronal Activity and Compensatory Remodeling of Inhibitory Hippocampal Circuits in Mouse Models of Alzheimer\u2019s Disease. Neuron, https:\/\/doi.org\/10.1016\/j.neuron.2007.07.025 (2007).","DOI":"10.1016\/j.neuron.2007.07.025"},{"key":"64334_CR24","doi-asserted-by":"publisher","unstructured":"Lalonde, R., Fukuchi, K. I. & Strazielle, C. Neurologic and motor dysfunctions in APP transgenic mice. Rev. Neurosci., https:\/\/doi.org\/10.1515\/revneuro-2012-0041 (2012).","DOI":"10.1515\/revneuro-2012-0041"},{"key":"64334_CR25","doi-asserted-by":"publisher","unstructured":"Kobayashi, D. et al. BACE1 gene deletion: Impact on behavioral function in a model of Alzheimer\u2019s disease. Neurobiol. Aging, https:\/\/doi.org\/10.1016\/j.neurobiolaging.2007.01.002 (2008).","DOI":"10.1016\/j.neurobiolaging.2007.01.002"},{"key":"64334_CR26","doi-asserted-by":"publisher","unstructured":"Sherzai, D., Losey, T., Vega, S. & Sherzai, A. Seizures and dementia in the elderly: Nationwide inpatient sample 1999-2008. Epilepsy Behav., https:\/\/doi.org\/10.1016\/j.yebeh.2014.04.015 (2014).","DOI":"10.1016\/j.yebeh.2014.04.015"},{"key":"64334_CR27","doi-asserted-by":"publisher","unstructured":"Vossel, K. A. et al. Seizures and epileptiform activity in the early stages of Alzheimer disease. JAMA Neurol., https:\/\/doi.org\/10.1001\/jamaneurol.2013.136 (2013).","DOI":"10.1001\/jamaneurol.2013.136"},{"key":"64334_CR28","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1016\/j.brainres.2017.09.026","volume":"1677","author":"KE Reyes-Marin","year":"2017","unstructured":"Reyes-Marin, K. E. & Nu\u00f1ez, A. Seizure susceptibility in the APP\/PS1 mouse model of Alzheimer\u2019s disease and relationship with amyloid \u03b2 plaques. Brain Res. 1677, 93\u2013100 (2017).","journal-title":"Brain Res."},{"key":"64334_CR29","doi-asserted-by":"publisher","unstructured":"Maatuf, Y., Stern, E. A. & Slovin, H. Abnormal Population Responses in the Somatosensory Cortex of Alzheimer\u2019s Disease Model Mice. Sci. Rep., https:\/\/doi.org\/10.1038\/srep24560 (2016).","DOI":"10.1038\/srep24560"},{"key":"64334_CR30","doi-asserted-by":"publisher","unstructured":"Hong, S. et al. Complement and microglia mediate early synapse loss in Alzheimer mouse models. Science (80-.)., https:\/\/doi.org\/10.1126\/science.aad8373 (2016).","DOI":"10.1126\/science.aad8373"},{"key":"64334_CR31","doi-asserted-by":"publisher","unstructured":"Eles, J. R., Vazquez, A. L., Kozai, T. D. Y. & Cui, X. T. In vivo imaging of neuronal calcium during electrode implantation: Spatial and temporal mapping of damage and recovery. Biomaterials, https:\/\/doi.org\/10.1016\/j.biomaterials.2018.04.043 (2018).","DOI":"10.1016\/j.biomaterials.2018.04.043"},{"key":"64334_CR32","doi-asserted-by":"publisher","unstructured":"Piilgaard, H. & Lauritzen, M. Persistent increase in oxygen consumption and impaired neurovascular coupling after spreading depression in rat neocortex. J. Cereb. Blood Flow Metab., https:\/\/doi.org\/10.1038\/jcbfm.2009.73 (2009).","DOI":"10.1038\/jcbfm.2009.73"},{"key":"64334_CR33","doi-asserted-by":"publisher","unstructured":"Chang, J. C. et al. Biphasic direct current shift, haemoglobin desaturation and neurovascular uncoupling in cortical spreading depression. Brain, https:\/\/doi.org\/10.1093\/brain\/awp338 (2010).","DOI":"10.1093\/brain\/awp338"},{"key":"64334_CR34","doi-asserted-by":"publisher","unstructured":"Kn\u00f6pfel, T. Genetically encoded optical indicators for the analysis of neuronal circuits. Nature Reviews Neuroscience, https:\/\/doi.org\/10.1038\/nrn3293 (2012).","DOI":"10.1038\/nrn3293"},{"key":"64334_CR35","doi-asserted-by":"publisher","unstructured":"Gao, Y. R. et al. Time to wake up: Studying neurovascular coupling and brain-wide circuit function in the un-anesthetized animal. NeuroImage, https:\/\/doi.org\/10.1016\/j.neuroimage.2016.11.069 (2017).","DOI":"10.1016\/j.neuroimage.2016.11.069"},{"key":"64334_CR36","doi-asserted-by":"publisher","unstructured":"Sharp, P. S. et al. Comparison of stimulus-evoked cerebral hemodynamics in the awake mouse and under a novel anesthetic regime. Sci. Rep., https:\/\/doi.org\/10.1038\/srep12621 (2015).","DOI":"10.1038\/srep12621"},{"key":"64334_CR37","doi-asserted-by":"publisher","unstructured":"H\u00e9bert, F. et al. Cortical atrophy and hypoperfusion in a transgenic mouse model of Alzheimer\u2019s disease. Neurobiol. Aging, https:\/\/doi.org\/10.1016\/j.neurobiolaging.2012.11.022 (2013).","DOI":"10.1016\/j.neurobiolaging.2012.11.022"},{"key":"64334_CR38","doi-asserted-by":"publisher","DOI":"10.1111\/j.1460-9568.2005.04347.x","author":"J Berwick","year":"2005","unstructured":"Berwick, J. et al. Neurovascular coupling investigated with two-dimensional optical imaging spectroscopy in rat whisker barrel cortex. Eur. J. Neurosci. https:\/\/doi.org\/10.1111\/j.1460-9568.2005.04347.x (2005).","journal-title":"Eur. J. Neurosci."},{"key":"64334_CR39","doi-asserted-by":"publisher","unstructured":"Mayhew, J. et al. Spectroscopic analysis of changes in remitted illumination: The response to increased neural activity in brain. Neuroimage, https:\/\/doi.org\/10.1006\/nimg.1999.0460 (1999).","DOI":"10.1006\/nimg.1999.0460"}],"container-title":["Scientific Reports"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-64334-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-64334-4","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-64334-4.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,12,6]],"date-time":"2022-12-06T05:05:32Z","timestamp":1670303132000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41598-020-64334-4"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2020,5,5]]},"references-count":39,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2020,12]]}},"alternative-id":["64334"],"URL":"https:\/\/doi.org\/10.1038\/s41598-020-64334-4","relation":{"has-preprint":[{"id-type":"doi","id":"10.1101\/848713","asserted-by":"object"}]},"ISSN":["2045-2322"],"issn-type":[{"value":"2045-2322","type":"electronic"}],"subject":[],"published":{"date-parts":[[2020,5,5]]},"assertion":[{"value":"20 November 2019","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"14 April 2020","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"5 May 2020","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"7518"}}