The β-Secretase-Derived C-Terminal Fragment of βAPP, C99, But Not Aβ, Is a Key Contributor to Early Intraneuronal Lesions in Triple-Transgenic Mouse Hippocampus

Lauritzen, Inger; Pardossi‐Piquard, Raphaëlle; Bauer, Charlotte; Brigham, Elizabeth F.; Abraham, Jean-Daniel; Ranaldi, Sébastien; Fraser, Paul E.; George-Hyslop, Peter St; Thuc, Ophélia Le; Espin, V.; Chami, L.; Dunys, Julie; Checler, Frédéric

doi:10.1523/jneurosci.2775-12.2012

Cited by 178 publications

(219 citation statements)

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“…The adverse impact of β-CTF on synaptic plasticity and neuronal function has attracted increasing interest (35,(41)(42)(43)(44)58). In our present studies, β-CTF, but not α-CTF, had detrimental effects on neuronal function, although they only differ in the first 16 N-terminal residues (see Methods).…”

Section: 8mentioning

confidence: 53%

“…The increase in Rab5 + puncta size was likely due to enhanced activation of Rab5, i.e., GTP-Rab5 (22), which induces homotypic fusion of early endosomes, causing their enlargement (19, 22, 23, Accumulation of β-CTF (C99) induces synaptic toxicity with a detrimental effect on neuronal function (41)(42)(43)(58)(59)(60). To explore whether C99-induced changes might be reflected in endosome structure and function, we tested APP SWE -YFP and APP M596V -YFP; expression of APP SWE provided a means to markedly increase C99 (57), while APP M596V enabled us examine the effect of full-length APP in the absence of C99 (57).…”

Section: Rab5mentioning

confidence: 99%

“…Additionally, the γ-secretase inhibitor (GSI) semagacestat, which eliminates all Aβ species while increasing APP-CTF levels, has shown severe adverse effect in clinical trials, which is likely associated with APP CTFs in AD patients (13,14,39,40). APP CTFs have since been shown to induce neuronal dysfunction and cognitive deficits in animal models (41)(42)(43)(44).…”

Section: Introductionmentioning

confidence: 99%

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Amyloid precursor protein–mediated endocytic pathway disruption induces axonal dysfunction and neurodegeneration

Xu¹,

Weissmiller²,

White³

et al. 2016

Journal of Clinical Investigation

148

225

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R e s e a R c h a R t i c l e1 8 1 6jci.org Volume 126Number 5 May 2016 26, 54, 55). We assayed the level of GTP-Rab5 in brains of 12-monthold Ts65Dn and 2N mice following a published protocol (56). As previously reported (28), the level of full-length APP in Ts65Dn was approximately 1.5-fold than in 2N samples ( We next tested whether the increase in App gene dose in Ts65Dn BFCNs was responsible for enlargement of Rab5 + endosomes (Figure 1). By immunoblotting, the APP siRNA caused an approximately 30% reduction in the level of full-length APP, as compared with control siRNA ( Figure 2E). Rab5 + puncta in BFCNs treated with either the APP siRNA or control siRNA were analyzed (Figure 2, F and G) as in Figure 1. Large, sometimes lobulated Rab5 + puncta were seen in cultures treated with the control siRNA, whereas these structures were typically smaller and rounded in cultures treated with the APP siRNA ( Figure 2G). Treatment with the APP siRNA significantly reduced the size of Rab5 + puncta in Ts65Dn neurons to a value equivalent to that in 2N neurons ( Figure 2F). Thus, increased App gene dose is necessary for increased Rab5 activation and for early endosome enlargement in Ts65Dn neurons.Full-length APP and β-CTF caused enlargement of early endosomes in PC12 cells. To determine how increased APP expression caused an increase in Rab5 activation, we asked which APP product(s) were responsible (Supplemental Figure 1A). We transfected PC12M cells with full-length APP-GFP, C99-GFP (β-CTF), C83-GFP (α-CTF), or AICD-GFP and examined endosomes by live cell imaging (Supplemental Figure 1B). Bright foci of GFP + intracellular structures were present in PC12M cells that overexpressed APP-GFP or C99-GFP. In contrast, cells expressing C83-GFP or AICD-GFP showed diffuse, hazy signals for GFP, with occasional foci in C83-GFP cells. In APP-GFP and C99-GFP cells, the GFP + intracellular structures were, on average, approximately 2 μm 2 (Supplemental Figure 1E). GFP signals in C83-GFP or AICD-GFP cells contained speckled small puncta within the haze, as well as a small number of larger bright puncta, as seen in cells expressing C99-GFP and APP-GFP (Supplemental Figure 1B). However, the average puncta size in C83-GFP and AICD-GFP cells was approximately 1.2 and 1.3 μm 2 , respectively. Thus, overexpressing APP and β-CTF, but not α-CTF or AICD, routinely induced formation of enlarged, bright intracellular structures. We also tested two APP mutants: APP M596V and APP SWE . APP M596V , which abolishes β-secretase cleavage, prevents production of β-CTF (57); APP SWE enhances β-secretase cleavage to increase the level of β-CTF (57). Both induced the formation of enlarged intracellular structures (Supplemental Figure 1C).We examined colocalization of APP or C99 with Rab5 in cotransfection experiments; APP-mCherry with GFP-Rab5 WT ( Figure 3B); C99-GFP with mCherry-Rab5 WT ( Figure 3C); and Rab5 + endosomes (26, 28, 37) was correlated with reduced endosomal trafficking and signaling of nerve growth factor (NGF), leading to degeneration...

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Section: 8mentioning

confidence: 53%

Section: Rab5mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Amyloid precursor protein–mediated endocytic pathway disruption induces axonal dysfunction and neurodegeneration

Xu¹,

Weissmiller²,

White³

et al. 2016

Journal of Clinical Investigation

148

225

View full text Add to dashboard Cite

show abstract

“…In agreement with these previous reports, the current study shows that the synaptic deficits observed in 3xTg‐AD mice at this early stage of the disease occur before the accumulation of plaques and tangles, suggesting that soluble oligomeric Aβ and phospho‐tau isoforms can induce profound synaptic deficits in 3xTg‐AD mice by 7‐8 months of age. Moreover, several studies have shown that the CTFs of APP are also important contributing factors leading to severe synaptic and memory deficits (Lauritzen et al., 2012). Similar to these studies, we found a profound increase in CTFs levels in hippocampal synaptosome samples from 7‐ to 8‐month‐old 3xTg‐AD mice, suggesting that the CTFs may have an important role in the synaptic impairments observed at this early age.…”

Section: Discussionmentioning

confidence: 99%

Impaired AMPA signaling and cytoskeletal alterations induce early synaptic dysfunction in a mouse model of Alzheimer's disease

et al. 2018

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SummaryAlzheimer's disease (AD) is a devastating neurodegenerative disorder that impairs memory and causes cognitive and psychiatric deficits. New evidences indicate that AD is conceptualized as a disease of synaptic failure, although the molecular and cellular mechanisms underlying these defects remain to be elucidated. Determining the timing and nature of the early synaptic deficits is critical for understanding the progression of the disease and for identifying effective targets for therapeutic intervention. Using single‐synapse functional and morphological analyses, we find that AMPA signaling, which mediates fast glutamatergic synaptic transmission in the central nervous system (CNS), is compromised early in the disease course in an AD mouse model. The decline in AMPA signaling is associated with changes in actin cytoskeleton integrity, which alters the number and the structure of dendritic spines. AMPA dysfunction and spine alteration correlate with the presence of soluble but not insoluble Aβ and tau species. In particular, we demonstrate that these synaptic impairments can be mitigated by Aβ immunotherapy. Together, our data suggest that alterations in AMPA signaling and cytoskeletal processes occur early in AD. Most important, these deficits are prevented by Aβ immunotherapy, suggesting that existing therapies, if administered earlier, could confer functional benefits.

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“…Moreover, unsuccessful efforts directed toward modifying Aβ production as a treatment for AD (Castello et al , 2014) have raised the possibility that other aspects of APP cleavage may be contributing to these metabolic changes. In this regard, increased levels of the C99 fragment have also been shown to contribute to AD pathogenesis (Lee et al , 2006; Lauritzen et al , 2012), suggesting a role for C99 in the early stages of pathogenesis.…”

Section: Introductionmentioning

confidence: 99%

Increased localization of APP‐C99 in mitochondria‐associated ER membranes causes mitochondrial dysfunction in Alzheimer disease

et al. 2017

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In the amyloidogenic pathway associated with Alzheimer disease (AD), the amyloid precursor protein (APP) is cleaved by β‐secretase to generate a 99‐aa C‐terminal fragment (C99) that is then cleaved by γ‐secretase to generate the β‐amyloid (Aβ) found in senile plaques. In previous reports, we and others have shown that γ‐secretase activity is enriched in mitochondria‐associated endoplasmic reticulum (ER) membranes (MAM) and that ER–mitochondrial connectivity and MAM function are upregulated in AD. We now show that C99, in addition to its localization in endosomes, can also be found in MAM, where it is normally processed rapidly by γ‐secretase. In cell models of AD, however, the concentration of unprocessed C99 increases in MAM regions, resulting in elevated sphingolipid turnover and an altered lipid composition of both MAM and mitochondrial membranes. In turn, this change in mitochondrial membrane composition interferes with the proper assembly and activity of mitochondrial respiratory supercomplexes, thereby likely contributing to the bioenergetic defects characteristic of AD.

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The β-Secretase-Derived C-Terminal Fragment of βAPP, C99, But Not Aβ, Is a Key Contributor to Early Intraneuronal Lesions in Triple-Transgenic Mouse Hippocampus

Cited by 178 publications

References 90 publications

Amyloid precursor protein–mediated endocytic pathway disruption induces axonal dysfunction and neurodegeneration

Amyloid precursor protein–mediated endocytic pathway disruption induces axonal dysfunction and neurodegeneration

Impaired AMPA signaling and cytoskeletal alterations induce early synaptic dysfunction in a mouse model of Alzheimer's disease

Increased localization of APP‐C99 in mitochondria‐associated ER membranes causes mitochondrial dysfunction in Alzheimer disease

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