<i>In Vivo</i>Assessment of Brain Interstitial Fluid with Microdialysis Reveals Plaque-Associated Changes in Amyloid-β Metabolism and Half-Life

Cirrito, John R.; May, Patrick C.; Odell, Mark; Taylor, Jennie; Parsadanian, Maia; Cramer, Jeffrey W.; Audia, James E.; Nissen, Jeffrey S.; Bales, Kelly R.; Paul, Steven M.; DeMattos, Ronald B.; Holtzman, David M.

doi:10.1523/jneurosci.23-26-08844.2003

Cited by 406 publications

(514 citation statements)

References 48 publications

Supporting

Mentioning

483

Contrasting

Unclassified

Order By: Relevance

“…Given that the ISF can be a source of toxic Aβ species, we determined whether antidepressant drugs reduced Aβ levels within this brain fluid. Dynamic changes in ISF Aβ levels can be measured over several days using in vivo microdialysis (21). This technique permits the animals to be awake with freedom of movement during drug administration and sample collection.…”

Section: Resultsmentioning

confidence: 99%

Serotonin signaling is associated with lower amyloid-β levels and plaques in transgenic mice and humans

Cirrito

Disabato²,

Restivo³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

314

307

View full text Add to dashboard Cite

Aggregation of amyloid-β (Aβ) as toxic oligomers and amyloid plaques within the brain appears to be the pathogenic event that initiates Alzheimer's disease (AD) lesions. One therapeutic strategy has been to reduce Aβ levels to limit its accumulation. Activation of certain neurotransmitter receptors can regulate Aβ metabolism. We assessed the ability of serotonin signaling to alter brain Aβ levels and plaques in a mouse model of AD and in humans. In mice, brain interstitial fluid (ISF) Aβ levels were decreased by 25% following administration of several selective serotonin reuptake inhibitor (SSRI) antidepressant drugs. Similarly, direct infusion of serotonin into the hippocampus reduced ISF Aβ levels. Serotonindependent reductions in Aβ were reversed if mice were pretreated with inhibitors of the extracellular regulated kinase (ERK) signaling cascade. Chronic treatment with an SSRI, citalopram, caused a 50% reduction in brain plaque load in mice. To test whether serotonin signaling could impact Aβ plaques in humans, we retrospectively compared brain amyloid load in cognitively normal elderly participants who were exposed to antidepressant drugs within the past 5 y to participants who were not. Antidepressant-treated participants had significantly less amyloid load as quantified by positron emission tomography (PET) imaging with Pittsburgh Compound B (PIB). Cumulative time of antidepressant use within the 5-y period preceding the scan correlated with less plaque load. These data suggest that serotonin signaling was associated with less Aβ accumulation in cognitively normal individuals.microdialysis | selective serotonin reuptake inhibitor antidepressants | late-life depression A myloid-β (Aβ) dysregulation appears to initiate the pathogenesis of Alzheimer's disease (AD) with a cascade of downstream factors that exacerbate and propagate neuronal injury (1). Aβ can accumulate as toxic plaques and soluble oligomers in the brains of individuals with AD a decade or more before the initial symptoms are identified (2). The concentration of Aβ is a critical factor determining if and when it will aggregate into these toxic structures; high concentrations of Aβ are more prone to convert from its normal soluble form into these multimeric conformations (3). Aβ is formed within neurons by sequential cleavage of the amyloid precursor protein (APP) by two enzymes, β-secretase and then γ-secretase. Alternatively, α-secretase can cleave APP within the Aβ sequence, which precludes the peptide from being formed at all. The enzymes and mechanisms that produce Aβ have been well characterized; however, the mechanisms that regulate Aβ production and levels are only partly understood. Understanding the cellular processes that regulate Aβ levels may provide greater insight into disease pathogenesis and suggest new avenues to treat or prevent AD.Synaptic activity is one key regulator of brain Aβ production. Depolarization and subsequent synaptic transmission causes Aβ to be produced presynaptically and then secreted into the brain extracel...

show abstract

Section: Resultsmentioning

confidence: 99%

Serotonin signaling is associated with lower amyloid-β levels and plaques in transgenic mice and humans

Cirrito

Disabato²,

Restivo³

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

314

307

View full text Add to dashboard Cite

show abstract

“…Animals were recovered after surgery before tracer studies. The experiments were performed before substantial chronic processes occurred, as assessed by histological analysis of tissue, i.e., negative staining for astrocytes (glial fibrillar acidic protein) and activated microglia (anti-phosphotyrosine), but allowing time for the BBB repair for large molecules, as reported previously (Cirrito et al, 2003;Deane et al, 2004). Isotope mixture (0.5 l) containing 125 I-labeled test molecule at 40 nM and 14 C-inulin was injected over 5 min via an ultra micropump with a micro4-controller (World Precision Instruments, Sarasota, FL) into brain ISF.…”

Section: Methodsmentioning

confidence: 99%

IgG-Assisted Age-Dependent Clearance of Alzheimer's Amyloid β Peptide by the Blood–Brain Barrier Neonatal Fc Receptor

Deane¹,

Sagare²,

Hamm³

et al. 2005

J. Neurosci.

209

211

View full text Add to dashboard Cite

“…Interestingly, recent data indicated a decreased rate of A␤ clearance in the AD brain rather than increased production (8,9). The half-life time of A␤ is ϳ8 -12 h in human cerebrospinal fluid and 3-4 h in the interstitial fluid of mouse brain, indicating efficient clearance mechanisms that counteract the production of A␤ (9,10,38). The clearance of A␤ from the brain involves internalization via pinocytosis or receptor-mediated endocytosis/phagocytosis (13-15, 39) and subsequent degradation in the endosomal/lysosomal compartments (40), transcytosis and drainage via the blood-brain barrier to the vasculature (12,41), and proteolytic degradation of extracellular A␤ by cell surface-localized and secreted proteases (21,28,36).…”

Section: Discussionmentioning

confidence: 99%

Phosphorylation of Amyloid-β Peptide at Serine 8 Attenuates Its Clearance via Insulin-degrading and Angiotensin-converting Enzymes

Kumar

Singh

Hinze

et al. 2012

Journal of Biological Chemistry

View full text Add to dashboard Cite

Background: Amyloid-␤ peptide (A␤) is degraded by different proteases. We recently demonstrated phosphorylation of A␤. Results: Phosphorylation of A␤ decreases its clearance by microglial BV-2 cells and selectively inhibits the cleavage by insulindegrading and angiotensin-converting enzymes. Conclusion: Phosphorylation at Ser-8 negatively regulates A␤ degradation. Significance: Phosphorylation could play a dual role in A␤ metabolism. It decreases the clearance by microglial cells and also promotes A␤ aggregation. Accumulation of amyloid-␤ peptides (A␤) in the brain is a common pathological feature of Alzheimer disease (AD).Aggregates of A␤ are neurotoxic and appear to be critically involved in the neurodegeneration during AD pathogenesis. Accumulation of A␤ could be caused by increased production, as indicated by several mutations in the amyloid precursor protein or the ␥-secretase components presenilin-1 and presenilin-2 that cause familial early-onset AD. However, recent data also indicate a decreased clearance rate of A␤ in AD brains. We recently demonstrated that A␤ undergoes phosphorylation by extracellular or cell surface-localized protein kinase A, leading to increased aggregation. Here, we provide evidence that phosphorylation of monomeric A␤ at Ser-8 also decreases its clearance by microglial cells. By using mass spectrometry, we demonstrate that phosphorylation at Ser-8 inhibited the proteolytic degradation of monomeric A␤ by the insulin-degrading enzyme, a major A␤-degrading enzyme released from microglial cells. Phosphorylation also decreased the degradation of A␤ by the angiotensin-converting enzyme. In contrast, A␤ degradation by plasmin was largely unaffected by phosphorylation. Thus, phosphorylation of A␤ could play a dual role in A␤ metabolism. It decreases its proteolytic clearance and also promotes its aggregation. The inhibition of extracellular A␤ phosphorylation, stimulation of protease expression and/or their proteolytic activity could be explored to promote A␤ degradation in AD therapy or prevention.Alzheimer disease (AD) 3 is characterized by the progressive deposition of amyloid-␤ peptides (A␤) in the brain (1, 2). A␤ derives from proteolytic processing of the amyloid precursor protein involving sequential cleavages by enzymes called ␤-and ␥-secretases (3, 4). A critical role of A␤ in the pathogenesis of AD is strongly supported by several mutations within the genes encoding the amyloid precursor protein itself or the two presenilins that represent the proteolytically active components of the ␥-secretase complex. All of these mutations affect the production and/or aggregation of A␤ and cause early-onset forms of familial AD (5-7). Although early-onset familial AD appears to be commonly associated with an elevated production of aggregation-prone A␤ variants, it remains unclear whether increased A␤ generation also contributes to the much more common form of late-onset AD. Recent evidence rather indicated a decreased clearance rate of A␤ in AD compared with control brains (8 -10).Several...

show abstract

In VivoAssessment of Brain Interstitial Fluid with Microdialysis Reveals Plaque-Associated Changes in Amyloid-β Metabolism and Half-Life

Cited by 406 publications

References 48 publications

Serotonin signaling is associated with lower amyloid-β levels and plaques in transgenic mice and humans

Serotonin signaling is associated with lower amyloid-β levels and plaques in transgenic mice and humans

IgG-Assisted Age-Dependent Clearance of Alzheimer's Amyloid β Peptide by the Blood–Brain Barrier Neonatal Fc Receptor

Phosphorylation of Amyloid-β Peptide at Serine 8 Attenuates Its Clearance via Insulin-degrading and Angiotensin-converting Enzymes

Contact Info

Product

Resources

About