title: In vivoDifferential Brain Clearance and Catabolism of Monomeric and Oligomeric Alzheimer's Aβ protein.
abstract: Amyloid β (Aβ) is the major constituent of the brain deposits found in parenchymal plaques and cerebral blood vessels of patients with Alzheimer's disease (AD). Several lines of investigation support the notion that synaptic pathology, one of the strongest correlates to cognitive impairment, is related to the progressive accumulation of neurotoxic Aβ oligomers. Since the process of oligomerization/fibrillization is concentration-dependent, it is highly reliant on the homeostatic mechanisms that regulate the steady state levels of Aβ influencing the delicate balance between rate of synthesis, dynamics of aggregation, and clearance kinetics. Emerging new data suggest that reduced Aβ clearance, particularly in the aging brain, plays a critical role in the process of amyloid formation and AD pathogenesis. Using well-defined monomeric and low molecular mass oligomeric Aβ1-40 species stereotaxically injected into the brain of C57BL/6 wild-type mice in combination with biochemical and mass spectrometric analyses in CSF, our data clearly demonstrate that Aβ physiologic removal is extremely fast and involves local proteolytic degradation leading to the generation of heterogeneous C-terminally cleaved proteolytic products, while providing clear indication of the detrimental role of oligomerization for brain Aβ efflux. Immunofluorescence confocal microscopy studies provide insight into the cellular pathways involved in the brain removal and cellular uptake of Aβ. The findings indicate that clearance from brain interstitial fluid follows local and systemic paths and that in addition to the blood-brain barrier, local enzymatic degradation and the bulk flow transport through the choroid plexus into the CSF play significant roles. Our studies highlight the diverse factors influencing brain clearance and the participation of various routes of elimination opening up new research opportunities for the understanding of altered mechanisms triggering AD pathology and for the potential design of combined therapeutic strategies.
authors.affiliation: Department of Pathology, New York University School of Medicine New York, NY, USA.
authors.forename: Farron L
authors.initials: FL
authors.lastname: McIntee
authors.affiliation: Department of Pathology, New York University School of Medicine New York, NY, USA.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Giannoni
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, New York University School of MedicineNew York, NY, USA; Kimmel Center for Biology and Medicine at the Skirball Institute, New York University School of MedicineNew York, NY, USA.
authors.forename: Steven
authors.initials: S
authors.lastname: Blais
authors.affiliation: Radiation Safety Office, New York University School of Medicine New York, NY, USA.
authors.forename: George
authors.initials: G
authors.lastname: Sommer
authors.affiliation: Department of Biochemistry and Molecular Pharmacology, New York University School of MedicineNew York, NY, USA; Kimmel Center for Biology and Medicine at the Skirball Institute, New York University School of MedicineNew York, NY, USA.
authors.forename: Thomas A
authors.initials: TA
authors.lastname: Neubert
authors.affiliation: Department of Pathology, New York University School of Medicine New York, NY, USA.
authors.forename: Agueda
authors.initials: A
authors.lastname: Rostagno
authors.affiliation: Department of Pathology, New York University School of MedicineNew York, NY, USA; Department of Psychiatry, New York University School of MedicineNew York, NY, USA.
authors.forename: Jorge
authors.initials: J
authors.lastname: Ghiso
keywords: Aβ brain efflux; Aβ brain homeostasis; cerebrospinal fluid; local proteolytic degradation; stereotaxic intra-cerebral injection; targeted mass spectrometric analysis