Oligomerization of Alzheimer's β-Amyloid within Processes and Synapses of Cultured Neurons and Brain

Takahashi, Riku; Almeida, Cláudia G.; Kearney, Patrick F.; Yu, Fangmin; Lin, Michael; Milner, Teresa A.; Gouras, Gunnar K.

doi:10.1523/jneurosci.5167-03.2004

Cited by 414 publications

(371 citation statements)

References 48 publications

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“…21. Intraneuronal accumulation of Aβ within distal processes and synaptic compartment 45 leads to the generation of free radicals 46 . These reactive species, in turn, disrupt the electron transport chain thus leading to mitochondrial dysfunction and consequent cytochrome c release from the outer membrane.…”

Section: Discussionmentioning

confidence: 99%

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: 99%

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

et al. 2010

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“…For example, oA␤ has been observed in association with membranous organelles as well as in the cytoplasm of neuronal processes either in association with microtubules or in empty areas within axonal processes (13). Furthermore, oA␤ is reported to be toxic when introduced into the cytosol of cultured primary neurons (18).…”

Section: Discussionmentioning

confidence: 99%

“…Intracellular A␤ was first described by Wertkin et al (11). Immunogold electron microscopy showed that intraneuronal A␤ is pre-and postsynaptically enriched in both AD human brain and AD transgenic animal models in association with dystrophic neurites and abnormal synaptic morphology (12)(13)(14). Spatial and temporal analyses of intraneuronal oA␤ accumulation show that it precedes plaque formation in both AD animal models and Down's syndrome patients, suggesting that oA␤ is an early intracellular toxic agent in AD (14, 15).…”

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confidence: 99%

Disruption of fast axonal transport is a pathogenic mechanism for intraneuronal amyloid beta

Pigino

Morfini

Atagi

et al. 2009

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

193

172

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The pathological mechanism by which A␤ causes neuronal dysfunction and death remains largely unknown. Deficiencies in fast axonal transport (FAT) were suggested to play a crucial role in neuronal dysfunction and loss for a diverse set of dying back neuropathologies including Alzheimer's disease (AD), but the molecular basis for pathological changes in FAT were undetermined. Recent findings indicate that soluble intracellular oligomeric A␤ (oA␤) species may play a critical role in AD pathology. Real-time analysis of vesicle mobility in isolated axoplasms perfused with oA␤ showed bidirectional axonal transport inhibition as a consequence of endogenous casein kinase 2 (CK2) activation. Conversely, neither unaggregated amyloid beta nor fibrillar amyloid beta affected FAT. Inhibition of FAT by oA␤ was prevented by two specific pharmacological inhibitors of CK2, as well as by competition with a CK2 substrate peptide. Furthermore, perfusion of axoplasms with active CK2 mimics the inhibitory effects of oA␤ on FAT. Both oA␤ and CK2 treatment of axoplasm led to increased phosphorylation of kinesin-1 light chains and subsequent release of kinesin from its cargoes. Therefore pharmacological modulation of CK2 activity may represent a promising target for therapeutic intervention in AD.Alzheimer's disease ͉ Axonal transport ͉ Beta amyloid oligomer ͉ CK2 ͉ Kinesin T he complex functional changes and histopathology of Alzheimer disease (AD) make it one of the most challenging disorders faced by modern medicine. Histopathological hallmarks of AD include distinctive extracellular and intracellular aggregates of amyloid beta (A␤) and tau (1, 2). Synaptic dysfunction and axonopathy appear to be the earliest lesions in AD as corroborated by reduced immunoreactivity of synaptophysin and other synaptic markers in terminal fields of brain-affected areas (3). AD-affected neurons appear to die eventually as a consequence of synaptic dysfunction and loss, following a typical dying-back pattern of neuronal degeneration.The amyloid hypothesis (4), a dominant concept in AD research for many years, has been revised in recent years to include the notion that smaller soluble A␤ aggregates may play an early and significant role in AD. Soluble oligomers of A␤ (oA␤) have been shown to be neurotoxic both in vivo and in vitro (5-7) as well as altering synaptic structure and function (8). Moreover, oA␤ levels correlate with impairments in cognitive function, learning, and memory (9, 10), but the molecular basis of these effects are uncertain. Intracellular A␤ was first described by Wertkin et al. (11). Immunogold electron microscopy showed that intraneuronal A␤ is pre-and postsynaptically enriched in both AD human brain and AD transgenic animal models in association with dystrophic neurites and abnormal synaptic morphology (12)(13)(14). Spatial and temporal analyses of intraneuronal oA␤ accumulation show that it precedes plaque formation in both AD animal models and Down's syndrome patients, suggesting that oA␤ is an early intracellular toxic agent i...

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“…11,14,64,70 Moreover, intraneuronal A␤ has been reported to substantially affect synaptic function 26 and integrity. 71 6) A chronic inflammation status. Previously, we reported widespread microglia activation within the hippocampal neuropil of APP751 SL / PS1 M146L mice that was only partly related to A␤ deposits.…”

Section: Alterations In Sipb Densities and Sipb Numbers In App751 Sl mentioning

confidence: 99%

Age-Related Loss of Synaptophysin Immunoreactive Presynaptic Boutons within the Hippocampus of APP751SL, PS1M146L, and APP751SL/PS1M146L Transgenic Mice

Rutten

Kolk

Schäfer

et al. 2005

The American Journal of Pathology

107

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Neuron and synapse loss are important features of the neuropathology of Alzheimer's disease (AD).Recently, we observed substantial age-related hippocampal neuron loss in APP751 SL /PS1 M146L transgenic mice but not in PS1 M146L mice. Here, we investigated APP751 SL mice, PS1 M146L mice, and APP751 SL / PS1 M146L mice for age-related alterations in synaptic integrity within hippocampal stratum moleculare of the dentate gyrus (SM), stratum lucidum of area CA3 (SL), and stratum radiatum of area CA1-2 (SR) by analyzing densities and numbers of synaptophysinimmunoreactive presynaptic boutons (SIPBs). Wildtype mice, APP751 SL mice and PS1 M146L mice showed similar amounts of age-related SIPB loss within SM, and no SIPB loss within SL. Both APP751 SL mice and PS1 M146L mice showed age-related SIPB loss within SR. Importantly, APP751 SL /PS1 M146L mice displayed the severest age-related SIPB loss within SM, SL, and SR, even in regions free of extracellular A␤ deposits. Together, these mouse models offer a unique framework to study the impact of several molecular and cellular events caused by mutant APP and/or mutant PS1 on age-related alterations in synaptic integrity. Alzheimer's disease (AD) is a progressive neurodegenerative disorder comprising cognitive and memory deterioration, progressive impairment of activities of daily living, and several neuropsychiatric symptoms. 1 The neuropathology of AD is characterized by disturbances in neural circuits, such as loss of neurons and synapses, and by protein aggregations of ␤-amyloid and hyperphosphorylated tau. 2-4 Accumulating evidence has indicated a crucial role for failure and loss of synapses in AD pathophysiology. 2,4,[5][6][7] Postmortem morphological studies on AD neuropathology have demonstrated significantly reduced synaptic connectivity in brain regions such as the neocortex and hippocampus. 3,6,7 Reductions in synaptic densities showed a strong correlation with cognitive decline in AD. 5 However, the reasons for the reduced connectivity in AD remain poorly understood. 8 According to the "␤-amyloid (A␤) hypothesis of AD," A␤ accumulation is the primary driving force in AD pathogenesis. This hypothesis is supported by the fact that mutations in the amyloid precursor protein (APP) and in presenilin (PS) 1 and PS2, causing early-onset cases of AD, modify APP processing and result in enhanced generation of A␤. 4 We have developed a transgenic mouse model of AD expressing human mutant APP751 (carrying the Swedish and London mutations KM670/671NL and

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Oligomerization of Alzheimer's β-Amyloid within Processes and Synapses of Cultured Neurons and Brain

Cited by 414 publications

References 48 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

Disruption of fast axonal transport is a pathogenic mechanism for intraneuronal amyloid beta

Age-Related Loss of Synaptophysin Immunoreactive Presynaptic Boutons within the Hippocampus of APP751SL, PS1M146L, and APP751SL/PS1M146L Transgenic Mice

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