Impaired β-Amyloid Secretion in Alzheimer's Disease Pathogenesis

Tampellini, Davide; Rahman, Nawreen; Lin, Michael; Capetillo-Zárate, Estibaliz; Gouras, Gunnar K.

doi:10.1523/jneurosci.2986-11.2011

Cited by 36 publications

(30 citation statements)

References 39 publications

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“…Our findings demonstrate that, under normal conditions, intracellular Aβ (including Aβ 42 and Aβ 40 ) is mainly associated with cytosolic structures and, to a large extent, is secreted from the cells. They may also suggest that deficits in secretion or lysosomal processing would result in intracellular Aβ accumulation and its translocation to the cellular organelles, as seen in AD and its models [12,21,52,53]. Our finding may contribute to better understanding of AD pathogenesis, and may help develop new therapeutic strategies against AD (reviewed in [54]).…”

Section: Discussionmentioning

confidence: 80%

“…It has been reported recently that Aβ –related synapse damage and memory impairment in AD-transgenic mice correlated with intracellular levels of Aβ but not with plaque burden [20]. Moreover, cultured neurons from AD-transgenic mice showed reduced secretion and enhanced intracellular accumulation of Aβ [21]. Much evidence supports that the lysosomal system, a vacuolar compartment with acidic pH (3.5-6.0), is associated with Aβ generation and neurotoxicity [22-26].…”

Section: Introductionmentioning

confidence: 99%

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Intracellular distribution of amyloid beta peptide and its relationship to the lysosomal system

Zheng

Cedazo-Minguez

Hallbeck

et al. 2012

Transl Neurodegener

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BackgroundAmyloid beta peptide (Aβ) is the main component of extraneuronal senile plaques typical of Alzheimer’s disease (AD) brains. Although Aβ is produced by normal neurons, it is shown to accumulate in large amounts within neuronal lysosomes in AD. We have recently shown that under normal conditions the majority of Aβ is localized extralysosomally, while oxidative stress significantly increases intralysosomal Aβ content through activation of macroautophagy. It is also suggested that impaired Aβ secretion and resulting intraneuronal increase of Aβ can contribute to AD pathology. However, it is not clear how Aβ is distributed inside normal neurons, and how this distribution is effected when Aβ secretion is inhibited.MethodsUsing retinoic acid differentiated neuroblastoma cells and neonatal rat cortical neurons, we studied intracellular distribution of Aβ by double immunofluorescence microscopy for Aβ40 or Aβ42 and different organelle markers. In addition, we analysed the effect of tetanus toxin-induced exocytosis inhibition on the intracellular distribution of Aβ.ResultsUnder normal conditions, Aβ was found in the small cytoplasmic granules in both neurites and perikarya. Only minor portion of Aβ was colocalized with trans-Golgi network, Golgi-derived vesicles, early and late endosomes, lysosomes, and synaptic vesicles, while the majority of Aβ granules were not colocalized with any of these structures. Furthermore, treatment of cells with tetanus toxin significantly increased the amount of intracellular Aβ in both perikarya and neurites. Finally, we found that tetanus toxin increased the levels of intralysosomal Aβ although the majority of Aβ still remained extralysosomally.ConclusionOur results indicate that most Aβ is not localized to Golgi-related structures, endosomes, lysosomes secretory vesicles or other organelles, while the suppression of Aβ secretion increases intracellular intra- and extralysosomal Aβ.

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Section: Discussionmentioning

confidence: 80%

Section: Introductionmentioning

confidence: 99%

Intracellular distribution of amyloid beta peptide and its relationship to the lysosomal system

Zheng

Cedazo-Minguez

Hallbeck

et al. 2012

Transl Neurodegener

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“…Thus, in this work AD-like synapse damage tracked with intraneuronal Aβ and not at all with plaques. Remarkably, more recent data showed that neurons derived from APP mutant transgenic mice, but not wild type mice, showed declines in Aβ secretion with time in culture, concomitant with a build-up of intraneuronal Aβ (Tampellini et al, 2011). The declining levels of extracellular Aβ in brains of APP mutant mice with aging assayed by in vivo microdialysis (Hong et al, 2011) could support such declining secretion.…”

Section: Discussionmentioning

confidence: 99%

Critical role of intraneuronal Aβ in Alzheimer's disease: Technical challenges in studying intracellular Aβ

2012

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Aims Multiple lines of evidence have implicated β-amyloid (Aβ) in the pathogenesis of Alzheimer’s disease (AD). However, the mechanism(s) whereby Aβ is involved in the disease process remains unclear. The dominant hypothesis in AD has been that Aβ initiates the disease via toxicity from secreted, extracellular Aβ aggregates. More recently, an alternative hypothesis has emerged focusing on a pool of Aβ that accumulates early on within AD vulnerable neurons of the brain. Although the topic of intraneuronal Aβ has been of major interest in the field, technical difficulties in detecting intraneuronal Aβ have also made this topic remarkably controversial. Here we review evidence pointing to the critical role of intraneuronal Aβ in AD and provide insights both into challenges faced in detecting intracellular Aβ and the prion-like properties of Aβ. Main methods Immunoprecipitation and Western blot are used for Aβ detection. Key findings We highlight that a standard biochemical method can underestimate intraneuronal Aβ and that extracellular Aβ can up-regulate intracellular Aβ. We also show that detergent can remove intraneuronal Aβ. Significance There is a growing awareness that intraneuronal Aβ is a key pathogenic pool of Aβ involved in causing synapse dysfunction. Difficulties in detecting intraneuronal Aβ are an insufficient reason for ignoring this critical pool of Aβ.

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“…Similar age-associated reduction in eAß 1−x level was demonstrated in hAPP mice (Hong et al, 2011). Since eAß 1−x levels are closely related to synaptic activity its reduction in older APP SW and in four month old APP SW /PS1 L166P mice, that represent a more rapidly progressing model of Aß pathology can be interpreted as reduced ability of synapses to secret Aß to the ISF, which evidence was recently provided from studies on primary neuronal cultures derived from Tg2576 mice (Tampellini et al, 2011). …”

Section: Discussionmentioning

confidence: 99%

In vivo hippocampal microdialysis reveals impairment of NMDA receptor–cGMP signaling in APPSW and APPSW/PS1L166P Alzheimer’s transgenic mice

Duszczyk

Kuszczyk

Guridi

et al. 2012

Neurochemistry International

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Transgenic (Tg) mice overexpressing human amyloid precursor protein (APP) mutants reproduce features of early Alzheimer's disease (AD) including memory deficit, presence of ß-amyloid (Aß) oligomers, and age-associated formation of amyloid deposits. In this study we used hippocampal microdialysis to characterize the signaling of N-methyl-D-aspartic acid receptors (NMDA-Rs) in awake and behaving AD Tg mice. The NMDA-R signaling is central to hippocampal synaptic plasticity underlying memory formation and several lines of evidence implicate the role of Aß oligomers in effecting NMDA-R dysfunction. CA1 NMDA-Rs were stimulated by NMDA infused through reverse microdialysis while changes in the cyclic guanosine monophosphate (cGMP) concentration in the brain interstitial fluid (ISF) were used to determine NMDA-Rs responsiveness. While four months old wild type C57BL/6 mice mounted robust cGMP response to the NMDA challenge, the same stimulus failed to significantly change the cGMP level in four and 15 months old APPSW and four months old APPSW/PS1L166P Tg mice, which were all on C57BL/6 background. Lack of response to NMDA in AD Tg mice occurred in the absence of changes in expression levels of several synaptic proteins including synaptophysin, NR1 NMDA-R subunit and postsynaptic density protein 95, which indicates lack of profound synaptic degeneration. Aß oligomers were detected in all three AD Tg mice groups and their concentration in the hippocampus ranged from 40.5±3.6ng/g in four months old APPSW mice to 60.8±15.9ng/g in four months old APPSW/PS1L166P mice. Four months old APPSW mice had no Aß amylod plaques, while the other two AD Tg mice groups showed evidence of incipient Aß amyloid plaque formation. Our studies describes a novel approach useful to study the function of NMDA-Rs in awake and behaving AD Tg mice and demonstrate impairment of NMDA-R response in the presence of endogenously formed Aß oligomers but predating onset of Aß amyloidosis.

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Impaired β-Amyloid Secretion in Alzheimer's Disease Pathogenesis

Cited by 36 publications

References 39 publications

Intracellular distribution of amyloid beta peptide and its relationship to the lysosomal system

Intracellular distribution of amyloid beta peptide and its relationship to the lysosomal system

Critical role of intraneuronal Aβ in Alzheimer's disease: Technical challenges in studying intracellular Aβ

In vivo hippocampal microdialysis reveals impairment of NMDA receptor–cGMP signaling in APPSW and APPSW/PS1L166P Alzheimer’s transgenic mice

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