Synaptic Activity Regulates Interstitial Fluid Amyloid-β Levels In Vivo

Summary Aggregation of the amyloid-β (Aβ) peptide in the extracellular space of the brain is central to Alzheimer's disease pathogenesis. Aβ aggregation is concentration dependent and brain region specific. Utilizing in vivo microdialysis concurrently with field potential recordings, we demonstrate that Aβ levels in the brain interstitial fluid are dynamically and directly influenced by synaptic activity on a timescale of minutes to hours. Using an acute brain slice model, we show that the rapid effects of synaptic activity on Aβ levels are primarily related to synaptic vesicle exocytosis. These results suggest that synaptic activity may modulate a neurodegenerative disease process, in this case by influencing Aβ metabolism and ultimately region-specific Aβ deposition. The findings also have important implications for treatment development.

[1]  M. Staufenbiel,et al.  Extracellular amyloid formation and associated pathology in neural grafts , 2003, Nature Neuroscience.

[2]  Y. Kuo,et al.  β-Amyloid Directly Inhibits Human α4β2-Nicotinic Acetylcholine Receptors Heterologously Expressed in Human SH-EP1 Cells* , 2004, Journal of Biological Chemistry.

[3]  Benjamin J. Shannon,et al.  Molecular, Structural, and Functional Characterization of Alzheimer's Disease: Evidence for a Relationship between Default Activity, Amyloid, and Memory , 2005, The Journal of Neuroscience.

[4]  D. Holtzman,et al.  In Vivo Assessment of Brain Interstitial Fluid with Microdialysis Reveals Plaque-Associated Changes in Amyloid-β Metabolism and Half-Life , 2003, The Journal of Neuroscience.

[5]  D. Holtzman,et al.  Apolipoprotein E Markedly Facilitates Age-Dependent Cerebral Amyloid Angiopathy and Spontaneous Hemorrhage in Amyloid Precursor Protein Transgenic Mice , 2003, The Journal of Neuroscience.

[6]  R. S. Sloviter,et al.  Basal expression and induction of glutamate decarboxylase GABA in excitatory granule cells of the rat and monkey hippocampal dentate gyrus , 1996, The Journal of comparative neurology.

[7]  Christina A. Wilson,et al.  GSK-3α regulates production of Alzheimer's disease amyloid-β peptides , 2003, Nature.

[8]  E. Koo,et al.  Trafficking of cell-surface beta-amyloid precursor protein: evidence that a sorting intermediate participates in synaptic vesicle recycling. , 1997, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[9]  D. Borchelt,et al.  Environmental Enrichment Mitigates Cognitive Deficits in a Mouse Model of Alzheimer's Disease , 2005, The Journal of Neuroscience.

[10]  Mikio Shoji,et al.  Age-Dependent Changes in Brain, CSF, and Plasma Amyloid β Protein in the Tg2576 Transgenic Mouse Model of Alzheimer's Disease , 2001, The Journal of Neuroscience.

[11]  S. Squazzo,et al.  Evidence that production and release of amyloid beta-protein involves the endocytic pathway. , 1994, The Journal of biological chemistry.

[12]  J. Buxbaum,et al.  Alzheimer Amyloid Protein Precursor in the Rat Hippocampus: Transport and Processing through the Perforant Path , 1998, The Journal of Neuroscience.

[13]  N. Hooper,et al.  Muscarine enhances soluble amyloid precursor protein secretion in human neuroblastoma SH-SY5Y by a pathway dependent on protein kinase C(alpha), src-tyrosine kinase and extracellular signal-regulated kinase but not phospholipase C. , 2002, Brain research. Molecular brain research.

[14]  A. Roher,et al.  Evidence for Seeding of b-Amyloid by Intracerebral Infusion of Alzheimer Brain Extracts in b-Amyloid Precursor Protein-Transgenic Mice , 2000 .

[15]  D. Price,et al.  Disruption of Corticocortical Connections Ameliorates Amyloid Burden in Terminal Fields in a Transgenic Model of Aβ Amyloidosis , 2002, The Journal of Neuroscience.

[16]  R L Buckner,et al.  Functional neuroimaging studies of encoding, priming, and explicit memory retrieval. , 1998, Proceedings of the National Academy of Sciences of the United States of America.

[17]  Laurie A. Miller,et al.  Senile plaques in temporal lobe epilepsy , 1994, Acta Neuropathologica.

[18]  M. Walker,et al.  Characterization of the Tetanus Toxin Model of Refractory Focal Neocortical Epilepsy in the Rat , 2005, Epilepsia.

[19]  R. Malinow,et al.  APP Processing and Synaptic Function , 2003, Neuron.

[20]  Ilana S. Hairston,et al.  Environmental Enrichment Reduces Aβ Levels and Amyloid Deposition in Transgenic Mice , 2005, Cell.

[21]  D. Schoepp,et al.  Regulation of Neurotransmitter Release by Metabotropic Glutamate Receptors , 2000, Journal of neurochemistry.

[22]  T. Beach,et al.  Reduction of cortical amyloid β levels in guinea pig brain after systemic administration of physostigmine , 2001, Neuroscience Letters.

[23]  G L Shulman,et al.  INAUGURAL ARTICLE by a Recently Elected Academy Member:A default mode of brain function , 2001 .

[24]  M. Raichle,et al.  Searching for a baseline: Functional imaging and the resting human brain , 2001, Nature Reviews Neuroscience.

[25]  D. Borchelt,et al.  Environmental Enrichment Exacerbates Amyloid Plaque Formation in a Transgenic Mouse Model of Alzheimer Disease , 2003, Journal of neuropathology and experimental neurology.

[26]  J. Growdon,et al.  Release of amyloid beta-protein precursor derivatives by electrical depolarization of rat hippocampal slices. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[27]  Bruce J Aronow,et al.  ApoE and Clusterin Cooperatively Suppress Aβ Levels and Deposition Evidence that ApoE Regulates Extracellular Aβ Metabolism In Vivo , 2004, Neuron.

[28]  C. Cotman,et al.  Voluntary exercise protects against stress-induced decreases in brain-derived neurotrophic factor protein expression , 2004, Neuroscience.

[29]  W. Oertel,et al.  Treatment with the selective muscarinic ml agonist talsaclidine decreases cerebrospinal fluid levels of Aβ42 in patients with Alzheimer's disease , 2003, Amyloid : the international journal of experimental and clinical investigation : the official journal of the International Society of Amyloidosis.

[30]  J. Growdon,et al.  The selective muscarinic M1 agonist AF102B decreases levels of total Aβ in cerebrospinal fluid of patients with Alzheimer's disease , 2000, Annals of neurology.

[31]  S. Sisodia,et al.  Post-translational Processing and Turnover Kinetics of Presynaptically Targeted Amyloid Precursor Superfamily Proteins in the Central Nervous System* , 1998, The Journal of Biological Chemistry.

[32]  P. De Camilli,et al.  Tetanus Toxin Blocks the Exocytosis of Synaptic Vesicles Clustered at Synapses But Not of Synaptic Vesicles in Isolated Axons , 1999, The Journal of Neuroscience.

[33]  D. Wilkin,et al.  Neuron , 2001, Brain Research.

[34]  D. Selkoe.  Alzheimer's disease: genes, proteins, and therapy. , 2001, Physiological reviews.

[35]  D. Peterson,et al.  Evidence That Synaptically Released β-Amyloid Accumulates as Extracellular Deposits in the Hippocampus of Transgenic Mice , 2002, The Journal of Neuroscience.

[36]  P. Greengard,et al.  Alzheimer Amyloid Protein Precursor Is Localized in Nerve Terminal Preparations to Rab5-containing Vesicular Organelles Distinct from Those Implicated in the Synaptic Vesicle Pathway* , 1996, The Journal of Biological Chemistry.

[37]  T. Südhof.  alpha-Latrotoxin and its receptors: neurexins and CIRL/latrophilins. , 2001, Annual review of neuroscience.

[38]  A. Roher,et al.  Evidence for Seeding of β-Amyloid by Intracerebral Infusion of Alzheimer Brain Extracts in β-Amyloid Precursor Protein-Transgenic Mice , 2000, The Journal of Neuroscience.

[39]  T. Lanz,et al.  Studies of Aβ Pharmacodynamics in the Brain, Cerebrospinal Fluid, and Plasma in Young (Plaque-Free) Tg2576 Mice Using the γ-Secretase Inhibitor N2-[(2S)-2-(3,5-Difluorophenyl)-2-hydroxyethanoyl]-N1-[(7S)-5-methyl-6-oxo-6,7-dihydro-5H-dibenzo[b,d]azepin-7-yl]-L-alaninamide (LY-411575) , 2004, Journal of Pharmacology and Experimental Therapeutics.