title: Systemic Central Nervous System (CNS)-targeted Delivery of Neuropeptide Y (NPY) Reduces Neurodegeneration and Increases Neural Precursor Cell Proliferation in a Mouse Model of Alzheimer Disease.
abstract: Neuropeptide Y (NPY) is one of the most abundant protein transmitters in the central nervous system with roles in a variety of biological functions including: food intake, cardiovascular regulation, cognition, seizure activity, circadian rhythms, and neurogenesis. Reduced NPY and NPY receptor expression is associated with numerous neurodegenerative disorders including Alzheimer disease (AD). To determine whether replacement of NPY could ameliorate some of the neurodegenerative and behavioral pathology associated with AD, we generated a lentiviral vector expressing NPY fused to a brain transport peptide (apoB) for widespread CNS delivery in an APP-transgenic (tg) mouse model of AD. The recombinant NPY-apoB effectively reversed neurodegenerative pathology and behavioral deficits although it had no effect on accumulation of Aβ. The subgranular zone of the hippocampus showed a significant increase in proliferation of neural precursor cells without further differentiation into neurons. The neuroprotective and neurogenic effects of NPY-apoB appeared to involve signaling via ERK and Akt through the NPY R1 and NPY R2 receptors. Thus, widespread CNS-targeted delivery of NPY appears to be effective at reversing the neuronal and glial pathology associated with Aβ accumulation while also increasing NPC proliferation. Overall, increased delivery of NPY to the CNS for AD might be an effective therapy especially if combined with an anti-Aβ therapeutic.
authors.affiliation: From the Departments of Neuroscience and.
authors.forename: Brian
authors.initials: B
authors.lastname: Spencer
authors.affiliation: From the Departments of Neuroscience and.
authors.forename: Rewati
authors.initials: R
authors.lastname: Potkar
authors.affiliation: From the Departments of Neuroscience and; Pathology, University of California, San Diego, California 92102.
authors.forename: Jeff
authors.initials: J
authors.lastname: Metcalf
authors.affiliation: From the Departments of Neuroscience and.
authors.forename: Ivy
authors.initials: I
authors.lastname: Thrin
authors.affiliation: From the Departments of Neuroscience and.
authors.forename: Anthony
authors.initials: A
authors.lastname: Adame
authors.affiliation: From the Departments of Neuroscience and.
authors.forename: Edward
authors.initials: E
authors.lastname: Rockenstein
authors.affiliation: From the Departments of Neuroscience and; Pathology, University of California, San Diego, California 92102. Electronic address: emasliah@ucsd.edu.
authors.forename: Eliezer
authors.initials: E
authors.lastname: Masliah
mesh_terms: D000544:Alzheimer Disease / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology* / Q000628:therapy; D016229:Amyloid beta-Peptides / Q000378:metabolism; D000818:Animals; D001055:Apolipoproteins B / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation; D002490:Central Nervous System / Q000166:cytology* / Q000378:metabolism; D004195:Disease Models, Animal; D018014:Gene Transfer Techniques; D015316:Genetic Therapy; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D058953:Neural Stem Cells / Q000166:cytology*; D055495:Neurogenesis; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D009478:Neuropeptide Y / Q000235:genetics* / Q000378:metabolism; D051381:Rats
chemical_list: D016229:Amyloid beta-Peptides; D001055:Apolipoproteins B; D009478:Neuropeptide Y
keywords: Alzheimer disease; Aβ; NPY; blood-brain barrier; neurodegeneration; neurogenesis; neuropeptide; protein targeting