Dendritic spine loss in the hippocampus of young PDAPP and Tg2576 mice and its prevention by the ApoE2 genotype

Lanz, Thomas A.; Carter, D.B; Merchant, Kalpana

doi:10.1016/s0969-9961(03)00079-2

Cited by 204 publications

(153 citation statements)

References 36 publications

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“…This is supported by several lines of evidence, such as: i) hippocampal spine-mediated plasticity underlies learning and memory 7 ; ii) post-mortem hippocampus from Alzheimer patients shows a significant decrease in dendritic spine density compared to age-matched controls 8 and iii) transgenic mice expressing mutated forms of the amyloid precursor protein (APP), associated with familial Alzheimer's Disease, show age-dependent reductions in spine density, prior to plaque deposition 9 .…”

Section: Discussionmentioning

confidence: 89%

Caspase-3 triggers early synaptic dysfunction in a mouse model of Alzheimer's disease

et al. 2010

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SummarySynaptic loss is the best pathological correlate of the cognitive decline in Alzheimer's Disease; yet, the molecular mechanisms underlying synaptic failure are unknown. Here we report a non-apoptotic baseline caspase-3 activity in hippocampal dendritic spines, and an enhancement of this activity at the onset of memory decline in the Tg2576-APPswe mouse model of Alzheimer's Disease. We show that, in spines, caspase-3 activates calcineurin which, in turn, triggers dephosphorylation and removal of the GluR1 subunit of AMPA-type receptor from post-synaptic sites. These molecular modifications lead to alterations of glutamatergic synaptic transmission and plasticity, and correlate with spine degeneration and a deficit in hippocampal-dependent memory. Importantly, pharmacological inhibition of caspase-3 activity in Tg2576 mice rescues the observed Alzheimerlike phenotypes. Therefore, we identify a novel caspase-3-dependent mechanism driving synaptic failure and contributing to cognitive dysfunction in Alzheimer's Disease. These findings point to caspase-3 as possible avenues for pharmacological therapy during early disease stages.Episodic hippocampal-dependent memory loss, the earliest clinical sign of Alzheimer's disease, is thought to be due to changes in synaptic function rather than neuronal loss 1,2 . Specifically, functional brain imaging studies revealed hippocampal mild abnormalities prior to clinical diagnosis and in the absence of structural brain atrophy, suggesting an altered functional connectivity of hippocampus at early stages of disease [3][4][5] .Dendritic spines are likely to be the first affected synaptic elements during early cognitive decline 6 . This is supported by several lines of evidence, such as: i) hippocampal spine-mediated plasticity underlies learning and memory 7 ; ii) post-mortem hippocampus from Alzheimer patients shows a significant decrease in dendritic spine density compared to age-matched controls 8 and iii) transgenic 3 mice expressing mutated forms of the amyloid precursor protein (APP), associated with familial Alzheimer's Disease, show age-dependent reductions in spine density, prior to plaque deposition 9 .Nevertheless, the molecular link between APP mutations triggering Alzheimer's Disease, and the occurrence of early spine loss remains elusive. Interestingly, a localized caspase-3 activity, causing synaptic failure, has been observed in vitro 10 , but the molecular mechanism linking caspase-3 activity to synaptic loss is far from being elucidated.Here, we analyzed caspase-3 activity in hippocampal synapses of the Tg2576 transgenic mouse model, harboring the human APPswe mutant allele linked to familial Alzheimer's Disease 11 . These mice develop early synaptic deficits 12 and several neuropathological features at older age, including amyloid plaques and dystrophic neurites 13 . Although Tg2576 mice lack neurofibrillary tangles and significant neuronal loss 14 , there is strong evidence that accumulation of the amyloid-β (Aβ) peptide, derived via APP proteolysis, is r...

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Section: Discussionmentioning

confidence: 89%

Caspase-3 triggers early synaptic dysfunction in a mouse model of Alzheimer's disease

et al. 2010

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“…However, our results, as well as the results of other studies (Urbanc et al, 2002;Spires et al, 2005) suggest that β-amyloid deposition may be associated with sublethal neuronal damage (i.e., synapse loss). Also, intracellular recordings from pyramidal neurons in Tg2576 mice show that β-amyloid plaques are associated with defects in cortical synaptic integration (Stern et al, 2004) and morphological studies in Tg2576 mice show that β-amyloid plaques are related to decreases in dendritic spine density (Lanz et al, 2003;Moolman et al, 2004;Tsai et al, 2004;Spires et al, 2005). Finally, Urbanc et al (2002) found that thioflavin-S positive plaques (fibrillar plaques) are selectively neurotoxic.…”

Section: Discussionmentioning

confidence: 99%

“…Synapse loss induced by Aβ remains a likely basis for the behavioral deficits observed in Tg2576 mice, since Aβ has been shown to disrupt neuronal function (Stern et al, 2004) and decrease dendritic spine density (Knowles et al, 1998;Lanz et al, 2003;Moolman et al, 2004;Tsai et al, 2004;Spires et al, 2005). However, studies using synaptophysin immunohistochemical staining under light microscopy have not produced consistent findings of synapse loss in Tg2576 mice.…”

Section: Introductionmentioning

confidence: 99%

Spatial relationship between synapse loss and β‐amyloid deposition in Tg2576 mice

Dong

Martin

Chambers

et al. 2006

J of Comparative Neurology

131

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Although there is evidence that β-amyloid impairs synaptic function, the relationship between β-amyloid and synapse loss is not well understood. In this study, we assessed synapse density within the hippocampus and the entorhinal cortex of Tg2576 mice at 6-18 months of age using stereological methods at both the light and electron microscope levels. Under light microscopy, we failed to find overall decreases in the density of synaptophysin-positive boutons in any brain areas selected, but bouton density was significantly decreased within 200 μm of compact β-amyloid plaques in the outer molecular layer of the dentate gyrus and layers II and III of the entorhinal cortex at 15-18 months of age in Tg 2576 mice. Under electron microscopy, we found overall decreases in synapse density in the outer molecular layer of the dentate gyrus at both 6-9 and 15-18 months of age, and in layers II and III of the entorhinal cortex at 15-18 months of age in Tg 2576 mice. However, we did not find overall changes in synapse density in the stratum radiatum of the CA1 subfield. Furthermore, in the two former brain areas, we found a correlation between lower synapse density and greater proximity to β-amyloid plaques. These results provide the first quantitative morphological evidence at the ultrastructure level of a spatial relationship between β-amyloid plaques and synapse loss within the hippocampus and the entorhinal cortex of Tg2576 mice.

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“…Dendritic spine loss has been documented in AD and in animal models, but previous studies associated such spine loss with late stages of the disease when amyloid plaques are present (Baloyannis, et al, 1992;Davidsson and Blennow, 1998;Einstein, et al, 1994;Ferrer and Gullotta, 1990;Moolman, et al, 2004;Probst, et al, 1983;Spires, et al, 2005). However, recent studies in young TG2576 transgenic mice expressing the APP-Swedish mutation observed reduced spine density prior to plaque deposition, suggesting that soluble forms of Aβ might confer synaptotoxic changes (Jacobsen, et al, 2006;Lanz, et al, 2003). This would be consistent with the finding that infusion of oligomeric Aβ into brain induced rapid and transient impairments in cognitive performance in rodents (Cleary, et al, 2005).…”

Section: Introductionmentioning

confidence: 99%

Rapid, concurrent alterations in pre- and postsynaptic structure induced by naturally-secreted amyloid-β protein

Calabrese

Shaked

Tabarean

et al. 2007

Molecular and Cellular Neuroscience

119

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In Alzheimer's disease increasing evidence attributes synaptic and cognitive deficits to soluble oligomers of amyloid β protein (Aβ), even prior to the accumulation of amyloid plaques, neurofibrillary tangles, and neuronal cell death. Here we show that within 1-2 hours picomolar concentrations of cell-derived, soluble Aβ induce specific alterations in pre-and postsynaptic morphology and connectivity in cultured hippocampal neurons. Clusters of presynaptic vesicle markers decreased in size and number at glutamatergic but not GABAergic terminals. Dendritic spines also decreased in number and became dysmorphic, as spine heads collapsed and/or extended long protrusions. Simultaneous time-lapse imaging of axon-dendrite pairs revealed that shrinking spines sometimes became disconnected from their presynaptic varicosity. Concomitantly, miniature synaptic potentials decreased in amplitude and frequency. Spine changes were prevented by blockers of nAChRs and NMDARs. Washout of Aβ within the first day reversed these spine changes. Further, spine changes reversed spontaneously by two days, because neurons acutely developed resistance to continuous Aβ exposure. Thus, rapid Aβ-induced synapse destabilization may underlie transient behavioral impairments in animal models, and early cognitive deficits in Alzheimer's patients.

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Dendritic spine loss in the hippocampus of young PDAPP and Tg2576 mice and its prevention by the ApoE2 genotype

Cited by 204 publications

References 36 publications

Caspase-3 triggers early synaptic dysfunction in a mouse model of Alzheimer's disease

Caspase-3 triggers early synaptic dysfunction in a mouse model of Alzheimer's disease

Spatial relationship between synapse loss and β‐amyloid deposition in Tg2576 mice

Rapid, concurrent alterations in pre- and postsynaptic structure induced by naturally-secreted amyloid-β protein

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