Beta-amyloid accumulation in APP mutant neurons reduces PSD-95 and GluR1 in synapses

Almeida, Cláudia G.; Tampellini, Davide; Takahashi, Riku; Greengard, Paul; Lin, Michael; Snyder, Eric M.; Gouras, Gunnar K.

doi:10.1016/j.nbd.2005.02.008

Cited by 349 publications

(308 citation statements)

References 43 publications

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Section: Detection Of Early Synaptic Deficits In Tg2576 Micesupporting

confidence: 83%

“…3c,d). Together with previous in vitro studies 22 , these in vivo results indicate that Aβ contributes to synaptic modifications, since alterations in GluR1 distribution and dendritic spine alterations were blocked by γ-secretase-dependent APP processing inhibition.Alterations of the PSD composition of hippocampal neurons in 3-month-old Tg2576 mice may lead to changes in glutamatergic synaptic transmission. We first evaluated basic synaptic transmission 6 by measuring input-output relationships of field excitatory post-synaptic potentials (fEPSPs) of CA1 pyramidal neurons evoked by stimulation of the Schaffer collateral pathway from acute hippocampal slices obtained from wild-type and Tg2576 mice.…”

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confidence: 83%

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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: Detection Of Early Synaptic Deficits In Tg2576 Micesupporting

confidence: 83%

supporting

confidence: 83%

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

et al. 2010

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“…In addition, the prevention of the decrease in synaptic markers found in treated mice showed that lithium and rosiglitazone prevent synaptic failure found in models of AD. 42,43,74,75 These changes correlate with an enhanced performance in our memory flexibility test, suggesting that hippocampal synaptic function is improved under both treatment conditions.…”

Section: Discussionmentioning

confidence: 67%

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

2009

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“…Indeed, synaptic terminals have abundant mitochondria essential to meet the local demand (31), and the paucity of mitochondria leads to synaptic dysfunction in both dendrites and axons (21,32). Not coincidentally, synaptic abnormalities were reported in APPswe neurons and transgenic mice (33). Therefore, it is likely that APP overexpression, by down-regulating DLP1 and causing abnormal mitochondrial distribution, depletes local mitochondrial support at remote sites and causes synaptic dysfunction.…”

Section: Discussionmentioning

confidence: 99%

Amyloid-β overproduction causes abnormal mitochondrial dynamics via differential modulation of mitochondrial fission/fusion proteins

Wang

Siedlak

et al. 2008

Proc. Natl. Acad. Sci. U.S.A.

734

592

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Mitochondrial dysfunction is a prominent feature of Alzheimer disease but the underlying mechanism is unclear. In this study, we investigated the effect of amyloid precursor protein (APP) and amyloid ␤ on mitochondrial dynamics in neurons. Confocal and electron microscopic analysis demonstrated that Ϸ40% M17 cells overexpressing WT APP (APPwt M17 cells) and more than 80% M17 cells overexpressing APPswe mutant (APPswe M17 cells) displayed alterations in mitochondrial morphology and distribution. Specifically, mitochondria exhibited a fragmented structure and an abnormal distribution accumulating around the perinuclear area. These mitochondrial changes were abolished by treatment with ␤-site APP-cleaving enzyme inhibitor IV. From a functional perspective, APP overexpression affected mitochondria at multiple levels, including elevating reactive oxygen species levels, decreasing mitochondrial membrane potential, and reducing ATP production, and also caused neuronal dysfunction such as differentiation deficiency upon retinoic acid treatment. At the molecular level, levels of dynamin-like protein 1 and OPA1 were significantly decreased whereas levels of Fis1 were significantly increased in APPwt and APPswe M17 cells. Notably, overexpression of dynamin-like protein 1 in these cells rescued the abnormal mitochondrial distribution and differentiation deficiency, but failed to rescue mitochondrial fragmentation and functional parameters, whereas overexpression of OPA1 rescued mitochondrial fragmentation and functional parameters, but failed to restore normal mitochondrial distribution. Overexpression of APP or A␤-derived diffusible ligand treatment also led to mitochondrial fragmentation and reduced mitochondrial coverage in neuronal processes in differentiated primary hippocampal neurons. Based on these data, we concluded that APP, through amyloid ␤ production, causes an imbalance of mitochondrial fission/fusion that results in mitochondrial fragmentation and abnormal distribution, which contributes to mitochondrial and neuronal dysfunction.amyloid precursor protein ͉ DLP1 ͉ mitochondrial fragmentation ͉ OPA1 ͉ perinuclear accumulation

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Beta-amyloid accumulation in APP mutant neurons reduces PSD-95 and GluR1 in synapses

Cited by 349 publications

References 43 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

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

Amyloid-β overproduction causes abnormal mitochondrial dynamics via differential modulation of mitochondrial fission/fusion proteins

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