Widespread Changes in Dendritic Spines in a Model of Alzheimer's Disease

Abstract

The mechanism by which dementia occurs in patients with Alzheimer's disease (AD) is not known. We assessed changes in hippocampal dendritic spines of APP/PS1 transgenic mice that accumulate amyloid beta throughout the brain. Three-dimensional analysis of 21,507 dendritic spines in the dentate gyrus, a region crucial for learning and memory, revealed a substantial decrease in the frequency of large spines in plaque-free regions of APP/PS1 mice. Plaque-related dendrites also show striking alterations in spine density and morphology. However, plaques occupy only 3.9% of the molecular layer volume. Because large spines are considered to be the physical traces of long-term memory, widespread decrease in the frequency of large spines likely contributes to the cognitive impairments observed in this AD model.

Activation of Wnt signaling by lithium and rosiglitazone reduced spatial memory impairment and neurodegeneration in brains of an APPswe/PSEN1ΔE9 mouse model of Alzheimer's disease

“…Dendritic spines have been found to be targets of oligomeric Ab, 6,43 and in vivo APP and PS1 transgenic mice develop a reduction in spine density because of Ab. 45 The analysis that rosiglitazone treatments protect against the toxicity of an ApoE4 fragment and increase dendritic spine density 21 suggests that this could be a mechanism by which rosiglitazone overcomes synaptic impairment.…”

“…Wnt signaling activation reduces the amount of Ab oligomers in the hippocampus As oligomeric aggregates of Ab have proven to be synaptotoxic 4 and reduce synaptic function in vitro and in vivo, [42][43][44][45] we decided to evaluate the amount of Ab oligomers present in brains of APP-PS1 mice. First, we assessed the areas and distribution of aggregate positives with BSB, a derivative of Congo Red that is more prone to stain oligomers than fibrils.…”

Glutamate system, amyloid β peptides and tau protein: functional interrelationships and relevance to Alzheimer disease pathology

“…98,104 Organotypic hippocampal slices from wild-type mice and mice overexpressing mutant APP have also been used extensively to look at the effects of amyloid β on neuron morphology, spine density, long-term potentiation and long-term depression. 98,105,106 Knafo and colleagues 107 assessed changes in the morphology and density of dendritic spines from the dentate gyrus in mice expressing PS1 and Swedish APP (APP sw ), a form of APP with a mutation at the β-cleavage site that increases amyloid β production. These results showed that the proximity of amyloid β plaques to the dendrites affected spine density and shape compared with littermate control mice.…”

“…Thus, APP sw transgenic mice were unable to form synapses as readily as nontransgenic mice, an observation that correlates well with the cognitive deficit found in mice expressing APP/PS1. 107 As the loss of large spines is found throughout the dentate gyrus of the mutant APP transgenic mice, it is likely that soluble forms of amyloid β peptides, rather than amyloid β-containing neuritic plaques, are responsible for this morphological deficit.…”

“…135 Second, amyloid β can activate α 7 nicotinic receptors or NMDA receptors and increase Ca 2+ entry into the cell. This • Increase long-term depression 98,[108][109][110] • Decrease synaptic density and alter the morphology of dendritic spines 98,106,107,115 • Regulate glutamate uptake from the synapse 60,73,110,116,117 • Stimulate release of glutamate 117,118 • Increase endocytosis of AMPA and NMDA receptors 108,119 • Disrupt the postsynaptic density and prevent NMDA and AMPA receptors reaching the cell surface 120,121 • Increase tau phosphorylation/cell death [122][123][124][125][126] AMPA = α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; NMDA = N-methyl-D-aspartate.…”