Subcellular Topography of Neuronal Aβ Peptide in APPxPS1 Transgenic Mice

Langui, Dominique; Girardot, Nadège; Hachimi, Khalid Hamid El; Allinquant, Bernadette; Blanchard, Véronique; Pradier, Laurent; Duyckaerts, Charles

doi:10.1016/s0002-9440(10)63405-0

Cited by 153 publications

(126 citation statements)

References 68 publications

Supporting

Mentioning

102

Contrasting

Unclassified

Order By: Relevance

“…Moreover, immunogold labeling of N2a cells with an anti-A␤ antibody showed that A␤ peptides also were localized to MVBs (Fig. 3), consistent with previous reports (29,30). Proteins that are destined for lysosomal degradation are sorted from the early endosomes to intraluminal vesicles of the MVBs or late endosomes.…”

Section: A Fraction Of A␤ Peptides Is Localized To Mvbs and Is Releassupporting

confidence: 90%

Alzheimer's disease β-amyloid peptides are released in association with exosomes

Rajendran

Honsho

Zahn

et al. 2006

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

1,165

1,074

View full text Add to dashboard Cite

Although the exact etiology of Alzheimer's disease (AD) is a topic of debate, the consensus is that the accumulation of ␤-amyloid (A␤) peptides in the senile plaques is one of the hallmarks of the progression of the disease. The A␤ peptide is formed by the amyloidogenic cleavage of the amyloid precursor protein (APP) by ␤-and ␥-secretases. The endocytic system has been implicated in the cleavages leading to the formation of A␤. However, the identity of the intracellular compartment where the amyloidogenic secretases cleave and the mechanism by which the intracellularly generated A␤ is released into the extracellular milieu are not clear. Here, we show that ␤-cleavage occurs in early endosomes followed by routing of A␤ to multivesicular bodies (MVBs) in HeLa and N2a cells. Subsequently, a minute fraction of A␤ peptides can be secreted from the cells in association with exosomes, intraluminal vesicles of MVBs that are released into the extracellular space as a result of fusion of MVBs with the plasma membrane. Exosomal proteins were found to accumulate in the plaques of AD patient brains, suggesting a role in the pathogenesis of AD. multivesicular bodies ͉ rafts ͉ amyloid precursor protein ͉ ␤-secretase ͉ endocytosis A lzheimer's disease (AD) is a late-onset neurological disorder with progressive loss of memory and cognitive abilities as a result of excessive neurodegeneration (1). AD is characterized by extracellular aggregates of ␤-amyloid (A␤) peptides known as amyloid plaques (2). The A␤ peptide is derived from the sequential processing of the amyloid precursor protein (APP) by ␤-and ␥-secretases. ␤-secretase [(␤-APP cleaving enzyme (BACE)] is a type-1 transmembrane aspartyl protease and is mainly localized to endosomes, lysosomes and the transGolgi network (3). ␥-Secretase is a multicomponent complex that is composed of presenilin-1͞presenilin-2, nicastrin, Aph-1, and PEN-2 (4) and is localized to the early secretory (5, 6) and the endocytic compartments (7,8). Nonamyloidogenic processing of APP involves ␣-secretase that cleaves APP inside the A␤ region, giving rise to the ␣-cleaved ectodomain, thus precluding the formation of A␤ (9). Hence, the availability of APP to either ␣-or ␤-secretase determines whether A␤ peptide will be generated. Lateral organization of membranes (10) and subcellular localization (11, 12) of the substrate and the secretases have been documented to regulate A␤ generation. Recent work suggests that ␤-secretase associates with lipid rafts, liquid-ordered domains in the membrane (13,14), and that integrity of raft domains is required for ␤-cleavage of APP to occur (ref. 10; see, however, ref. 15). ␣-Cleavage, in contrast, occurs outside raft domains (10). The ␥-secretase complex is also raft-associated (16); hence, amyloidogenic processing of APP could occur in clustered raft domains to generate A␤ (10). Inhibition of endocytosis reduces ␤-cleavage but not ␣-cleavage, suggesting that ␤-cleavage mainly occurs in endosomes (10,11,(17)(18)(19). Accumulation of A␤ peptides in extracellular...

show abstract

Section: A Fraction Of A␤ Peptides Is Localized To Mvbs and Is Releassupporting

confidence: 90%

Alzheimer's disease β-amyloid peptides are released in association with exosomes

Rajendran

Honsho

Zahn

et al. 2006

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

1,165

1,074

View full text Add to dashboard Cite

show abstract

“…Specifically, it reconciles the known extracellular deposition of terminal amyloid plaques in AD patients or AD mouse models (15, 23) with numerous observations from AD patients (33), AD mouse models (34) and Aβ-transgenic Drosophila melanogaster flies (35) showing that Aβ species may also accumulate inside the cell, including MVBs (16,36,37), lysosomes or other vesicular compartments (38)(39)(40). The present observation of an intracellular route of amyloid plaque formation is consistent with observations that extracellular amyloid plaques typically contain a spectrum of proteins that are originally intracellular.…”

Section: Discussionsupporting

confidence: 52%

“…The present observation of an intracellular route of amyloid plaque formation is consistent with observations that extracellular amyloid plaques typically contain a spectrum of proteins that are originally intracellular. For instance, AD plaques commonly contain lysosomal proteases or molecular chaperones from the heat shock protein families Hsp70 or Hsp20 (17,36,(41)(42)(43).…”

Section: Discussionmentioning

confidence: 99%

Mechanism of amyloid plaque formation suggests an intracellular basis of Aβ pathogenicity

Friedrich

Tepper²,

Rönicke³

et al. 2010

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

280

220

View full text Add to dashboard Cite

The formation of extracellular amyloid plaques is a common patho-biochemical event underlying several debilitating human conditions, including Alzheimer’s disease (AD). Considerable evidence implies that AD damage arises primarily from small oligomeric amyloid forms of Aβ peptide, but the precise mechanism of pathogenicity remains to be established. Using a cell culture system that reproducibly leads to the formation of Alzheimer’s Aβ amyloid plaques, we show here that the formation of a single amyloid plaque represents a template-dependent process that critically involves the presence of endocytosis- or phagocytosis-competent cells. Internalized Aβ peptide becomes sorted to multivesicular bodies where fibrils grow out, thus penetrating the vesicular membrane. Upon plaque formation, cells undergo cell death and intracellular amyloid structures become released into the extracellular space. These data imply a mechanism where the pathogenic activity of Aβ is attributed, at least in part, to intracellular aggregates.

show abstract

“…29). Several APP derivatives accumulate in multivesicular bodies (MVBs), in transgenic animal models of amyloidosis (30,31), in Alzheimer disease (30), and in cell models (32). MVBs belong to the endocytic pathway (33); are at the crossroad of several cellular mechanisms such as membrane receptor recycling and protein degradation; and can release their intraluminal vesicles, known as exosomes (for review, see Refs.…”

mentioning

confidence: 99%

Alkalizing Drugs Induce Accumulation of Amyloid Precursor Protein By-products in Luminal Vesicles of Multivesicular Bodies

Vingtdeux

Hamdane

Loyens

et al. 2007

Journal of Biological Chemistry

178

166

View full text Add to dashboard Cite

Amyloid precursor protein (APP) metabolism is central to the pathogenesis of Alzheimer disease. We showed recently that the amyloid intracellular domain (AICD), which is released by ␥-secretase cleavage of APP C-terminal fragments (CTFs), is strongly increased in cells treated with alkalizing drugs (Vingtdeux, V., Hamdane, M., Bégard, S., Loyens, A., Delacourte, A., Beauvillain, J.-C., Buée, L., Marambaud, P., and Sergeant, N. Amyloid precursor protein (APP)3 metabolism is central to Alzheimer disease etiopathogenesis. Extracellular amyloid deposits, a neuropathological hallmark of Alzheimer disease, are composed of amyloid-␤ (A␤) peptides that derive from APP catabolism. APP is a type I transmembrane glycoprotein processed by an ␣-or a ␤-secretase to produce C-terminal fragments (CTFs) (for review, see Ref. 1). ␥-Secretase further processes APP-CTFs (2, 3), releasing A␤ from ␤-CTF and the amyloid intracellular domain (AICD or ⑀-CTF) from all APP-CTFs (2, 4 -8). Several lines of evidence suggest that AICD is a trans-regulating factor of gene expression (neprilysin, KAI1, APP, and glycogen synthase kinase-3␤) (9 -12). However, AICD is rapidly degraded and thus seldom detected (13). We showed recently that AICD is strongly increased upon treatment with alkalizing drugs, suggesting that the endosomal/lysosomal pathway regulates AICD degradation (14).The endosomal/lysosomal pathway is essential for A␤ production and APP catabolism. For instance, BACE-1 (beta-site APP-cleaving enzyme 1) resides within endosomes, and endocytosis of BACE-1 and APP is a prerequisite for generating A␤ (15-17). An acidic pH is necessary for optimal BACE-1 protease activity (18), and BACE-1 is degraded in lysosomes (19). The ␥-secretase activity has been localized at the endosomal/ lysosomal membrane (20 -23). Treatment with drugs that prevent endosomal/lysosomal acidification (24 -26) or deletion of the APP internalization motif (27, 28) dramatically reduces A␤ secretion.The endosomal/lysosomal system is likely to be altered in Alzheimer disease (for review, see Ref. 29). Several APP derivatives accumulate in multivesicular bodies (MVBs), in transgenic animal models of amyloidosis (30, 31), in Alzheimer disease (30), and in cell models (32). MVBs belong to the endocytic pathway (33); are at the crossroad of several cellular mechanisms such as membrane receptor recycling and protein degradation; and can release their intraluminal vesicles, known as exosomes (for review, see Refs. 34 -36). More recently, exosomes were demonstrated to contain A␤ peptides (37). Taken together, a growing body of evidence suggests that APP processing takes place mainly between the plasma membrane and late endosomal compartments such as multivesicular endosomes. Herein, we studied the localization of APP and its derivatives in SY5Y neuroblastoma cells stably overexpressing human APP and demonstrate that APP, APP-CTFs, and AICD accumulate in the luminal vesicles of multivesicular endosomes and are also found in exosomes.

show abstract

Subcellular Topography of Neuronal Aβ Peptide in APPxPS1 Transgenic Mice

Cited by 153 publications

References 68 publications

Alzheimer's disease β-amyloid peptides are released in association with exosomes

Alzheimer's disease β-amyloid peptides are released in association with exosomes

Mechanism of amyloid plaque formation suggests an intracellular basis of Aβ pathogenicity

Alkalizing Drugs Induce Accumulation of Amyloid Precursor Protein By-products in Luminal Vesicles of Multivesicular Bodies

Contact Info

Product

Resources

About