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      Neuronal activity regulates the regional vulnerability to amyloid-β deposition

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          Abstract

          Amyloid-β (Aβ) plaque deposition in specific brain regions is a major pathological hallmark of Alzheimer’fs disease (AD). However, the mechanism underlying the regional vulnerability to Aβ deposition in AD is unknown. Herein, we provide evidence that endogenous neuronal activity regulates the regional concentration of interstitial fluid (ISF) Aβ which drives local Aβ aggregation. Using in vivo microdialysis, we show that ISF Aβ levels in multiple brain regions of APP transgenic mice prior to plaque deposition were commensurate with the degree of subsequent plaque deposition and to the concentration of lactate, a marker of neuronal activity. Furthermore, unilateral vibrissae stimulation increased ISF Aβ, and unilateral vibrissae deprivation decreased ISF Aβ and lactate levels in contralateral barrel cortex. Long term unilateral vibrissae deprivation decreased amyloid plaque formation and growth. Our results suggest a mechanism to account for the vulnerability of specific brain regions to Aβ deposition in AD.

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          Most cited references32

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          Correlative memory deficits, Abeta elevation, and amyloid plaques in transgenic mice.

          Transgenic mice overexpressing the 695-amino acid isoform of human Alzheimer beta-amyloid (Abeta) precursor protein containing a Lys670 --> Asn, Met671 --> Leu mutation had normal learning and memory in spatial reference and alternation tasks at 3 months of age but showed impairment by 9 to 10 months of age. A fivefold increase in Abeta(1-40) and a 14-fold increase in Abeta(1-42/43) accompanied the appearance of these behavioral deficits. Numerous Abeta plaques that stained with Congo red dye were present in cortical and limbic structures of mice with elevated amounts of Abeta. The correlative appearance of behavioral, biochemical, and pathological abnormalities reminiscent of Alzheimer's disease in these transgenic mice suggests new opportunities for exploring the pathophysiology and neurobiology of this disease.
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            The role of apolipoprotein E in Alzheimer's disease.

            The epsilon4 allele of apolipoprotein E (APOE) is the major genetic risk factor for Alzheimer's disease (AD). Although there have been numerous studies attempting to elucidate the underlying mechanism for this increased risk, how apoE4 influences AD onset and progression has yet to be proven. However, prevailing evidence suggests that the differential effects of apoE isoforms on Abeta aggregation and clearance play the major role in AD pathogenesis. Other potential mechanisms, such as the differential modulation of neurotoxicity and tau phosphorylation by apoE isoforms as well as its role in synaptic plasticity and neuroinflammation, have not been ruled out. Inconsistent results among studies have made it difficult to define whether the APOE epsilon4 allele represents a gain of toxic function, a loss of neuroprotective function, or both. Therapeutic strategies based on apoE propose to reduce the toxic effects of apoE4 or to restore the physiological, protective functions of apoE.
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              APP processing and synaptic function.

              A large body of evidence has implicated Abeta peptides and other derivatives of the amyloid precursor protein (APP) as central to the pathogenesis of Alzheimer's disease (AD). However, the functional relationship of APP and its proteolytic derivatives to neuronal electrophysiology is not known. Here, we show that neuronal activity modulates the formation and secretion of Abeta peptides in hippocampal slice neurons that overexpress APP. In turn, Abeta selectively depresses excitatory synaptic transmission onto neurons that overexpress APP, as well as nearby neurons that do not. This depression depends on NMDA-R activity and can be reversed by blockade of neuronal activity. Synaptic depression from excessive Abeta could contribute to cognitive decline during early AD. In addition, we propose that activity-dependent modulation of endogenous Abeta production may normally participate in a negative feedback that could keep neuronal hyperactivity in check. Disruption of this feedback system could contribute to disease progression in AD.
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                Author and article information

                Journal
                9809671
                21092
                Nat Neurosci
                Nature neuroscience
                1097-6256
                1546-1726
                14 March 2011
                1 May 2011
                June 2011
                1 December 2011
                : 14
                : 6
                : 750-756
                Affiliations
                [1 ] Department of Neurology, Washington University School of Medicine, St. Louis, MO, 63110, USA
                [2 ] Department of Developmental Biology, Washington University School of Medicine, St. Louis, MO, 63110, USA
                [3 ] Department of Radiology, Washington University School of Medicine, St. Louis, MO, 63110, USA
                [4 ] Department of Anatomy and Neurobiology, Washington University School of Medicine, St. Louis, MO, 63110, USA
                [5 ] Department of Biomedical Engineering, Washington University School of Medicine, St. Louis, MO, 63110, USA
                [6 ] Hope Center for Neurological Disorders, Washington University School of Medicine, St. Louis, MO, 63110, USA
                [7 ] Charles F. and Joanne Knight Alzheimer’s Disease Research Center, Washington University School of Medicine, St. Louis, MO, 63110, USA
                Author notes
                To whom correspondence should be addressed: David M. Holtzman, M.D., Andrew B. and Gretchen P. Jones Professor and Chair, Department of Neurology, Washington University School of Medicine, 660 S. Euclid Ave. Campus Box 8111, Saint Louis, MO 63110, Administrator phone: (314) 747-0644, Office phone: (314) 362-9872, Fax: (314) 362-2244, holtzman@ 123456neuro.wustl.edu
                Article
                nihpa279971
                10.1038/nn.2801
                3102784
                21532579
                dacd2859-6a97-4cf7-b7bf-ba7e0c6d6c9b

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                History
                Funding
                Funded by: National Institute on Aging : NIA
                Funded by: National Institute of Neurological Disorders and Stroke : NINDS
                Award ID: R37 AG013956-16 ||AG
                Funded by: National Institute on Aging : NIA
                Funded by: National Institute of Neurological Disorders and Stroke : NINDS
                Award ID: P30 NS057105-05 ||NS
                Funded by: National Institute on Aging : NIA
                Funded by: National Institute of Neurological Disorders and Stroke : NINDS
                Award ID: K01 AG029524-05 ||AG
                Funded by: National Institute on Aging : NIA
                Funded by: National Institute of Neurological Disorders and Stroke : NINDS
                Award ID: F31 AG033452-03 ||AG
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                Neurosciences
                Neurosciences

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