Dendritic Spine Density, Morphology, and Fibrillar Actin Content Surrounding Amyloid-β Plaques in a Mouse Model of Amyloid-β Deposition

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-beta (A beta) peptide, either insoluble fibrillar A beta deposited into plaques or soluble nonfibrillar A beta species, can cause spine loss but the concurrent contributions of fibrillar A beta and nonfibrillar A beta 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 A beta deposition. Our approach allowed us to measure fibrillar A beta plaque content and an index of nonfibrillar A beta species concurrently. We found that spine density was reduced within 6 Km of the plaque perimeter, remaining spines were more compact, and F-actin content per spine was increased. Measures of fibrillar A beta plaque content were associated with reduced spine density near plaques, whereas measures of nonfibrillar A beta 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 A beta and that nonfibrillar A beta may exert spine toxicity through pathways not mediated by depolymerization of F-actin.