title: Dendritic spine density, morphology, and fibrillar actin content surrounding amyloid-β plaques in a mouse model of amyloid-β deposition.
abstract: Dendritic spines are the site of most excitatory synapses, the loss of which correlates with cognitive impairment in patients with Alzheimer disease. Substantial evidence indicates that amyloid-β (Aβ) peptide, either insoluble fibrillar Aβ deposited into plaques or soluble nonfibrillar Aβ species, can cause spine loss but the concurrent contributions of fibrillar Aβ and nonfibrillar Aβ to spine loss has not been previously assessed. We used multiple-label immunohistochemistry to measure spine density, size, and F-actin content surrounding plaques in the cerebral cortex in the PSAPP mouse model of Aβ deposition. Our approach allowed us to measure fibrillar Aβ plaque content and an index of nonfibrillar Aβ species concurrently. We found that spine density was reduced within 6 μm of the plaque perimeter, remaining spines were more compact, and F-actin content per spine was increased. Measures of fibrillar Aβ plaque content were associated with reduced spine density near plaques, whereas measures of nonfibrillar Aβ species were associated with reduced spine density and size but not altered F-actin content. These findings suggest that strategies to preserve dendritic spines in AD patients may need to address both nonfibrillar and fibrillar forms of Aβ and that nonfibrillar Aβ may exert spine toxicity through pathways not mediated by depolymerization of F-actin.
authors.affiliation: Translational Neuroscience Program, Department of Psychiatry, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: Caitlin M
authors.initials: CM
authors.lastname: Kirkwood
authors.forename: Jennifer
authors.initials: J
authors.lastname: Ciuchta
authors.forename: Milos D
authors.initials: MD
authors.lastname: Ikonomovic
authors.forename: Kenneth N
authors.initials: KN
authors.lastname: Fish
authors.forename: Eric E
authors.initials: EE
authors.lastname: Abrahamson
authors.forename: Patrick S
authors.initials: PS
authors.lastname: Murray
authors.forename: William E
authors.initials: WE
authors.lastname: Klunk
authors.forename: Robert A
authors.initials: RA
authors.lastname: Sweet
mesh_terms: D000199:Actins / Q000378:metabolism*; D000544:Alzheimer Disease / Q000235:genetics / Q000473:pathology*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics; D000818:Animals; D049229:Dendritic Spines / Q000378:metabolism* / Q000648:ultrastructure; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D021621:Imaging, Three-Dimensional; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000473:pathology / Q000648:ultrastructure*; D058225:Plaque, Amyloid / Q000378:metabolism* / Q000473:pathology; D053764:Presenilin-1 / Q000235:genetics
chemical_list: D000199:Actins; D016564:Amyloid beta-Protein Precursor; C508853:PSEN1 protein, human; D053764:Presenilin-1