Intracellular distribution of amyloid beta peptide and its relationship to the lysosomal system
© Zheng et al.; licensee BioMed Central Ltd. 2012
Received: 5 January 2012
Accepted: 13 September 2012
Published: 26 September 2012
Amyloid 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.
Using 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.
Under 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.
Our 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.
KeywordsAlzheimer disease Amyloid β-protein Colocalization Exocytosis Immunocytochemistry Lysosomes
The mechanisms behind Alzheimer disease (AD), the main cause of senile dementia, are poorly understood. One of the important hallmarks of AD is the formation of extracellular senile plaques, preferentially composed of amyloid beta-protein. The most common isoforms of Aβ are Aβ40 (90%) and Aβ42 (10%), the latter being more toxic, more prone to aggregation, more resistant to degradation, and specifically increases in all forms of familial AD.
Aβ is proteolytically cleaved from a large transmembrane amyloid precursor protein (APP) by β and γ secretases. APP is normally synthesized in the endoplasmic reticulum (ER) and transported to the Golgi apparatus. Eventually it can be trafficked from the trans-Golgi network (TGN) to the cell surface and secreted into extracellular space, recycled back to the Golgi complex for further packaging and trafficking or reinternalized from the cell surface into the endosomal-lysosomal system via endocytosis[6–8]. Aβ generation from APP is thought to occur in a variety of organelles where APP, β and γ secretase reside. Thus, Aβ has been found in many intracellular sites, such as ER, Golgi complexes, mitochondria, endosomes, lysosomes, multivesicular bodies (MVB), and cytosol (reviewed in). Autophagic vacuoles have also been shown involved in the production of Aβ.
The toxicity of Aβ and its involvement in senile plaque formation are considered important pathophysiological targets for primary prevention in AD (reviewed in). It has been proposed that senile plaques originate from intraneuronal Aβ as a result of its release after neuronal death. Intracellular Aβ has been pointed out to be involved in early stages of the disease, directly causing neurotoxicity and initiating AD pathology[12–19]. 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. Moreover, cultured neurons from AD-transgenic mice showed reduced secretion and enhanced intracellular accumulation of Aβ. 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]. In AD and experimental AD models, Aβ has been detected in abnormally enlarged endosomes[12, 17, 27], autophagosomes, and lysosomes[28–30].
Our previous studies showed that normobaric hyperoxia (a chronic, mild oxidative stress) enhanced macroautophagy, inducing intralysosomal Aβ accumulation, lysosomal membrane permeabilization and consequent apoptosis[29–32]. However, it is not clear how Aβ is distributed in relation to the lysosomal system and other organelles normally and how and why this distribution is changed in AD. Here we studied the relation of Aβ to the lysosomal vacuolar compartment (early and late endosomes, lysosomes and autolysosomes) as well as to cellular structures associated with related process of protein secretion (such as Golgi-derived secretory vesicles and synaptic vesicles) using double immunofluorescence microscopy (for Aβ and different organelle markers). RA-differentiated neuroblastoma cells and neonatal rat cortical neurons were used as in vitro models. Cells were cultured under normal conditions as well as in the presence of the exocytosis inhibitor, tetanus toxin (TeNT).
Materials and methods
Human neuroblastoma SH-SY5Y cell culture
Human SH-SY5Y neuroblastomacells were obtained from the American Type Culture Collection (Rockville, MD, USA) and cultured in Dulbecco’s Modified Eagle Medium (DMEM; Gibco, Paisley, UK) supplemented with 4500 mg/l glucose, 110 mg/l sodium pyruvate, 584 mg/l glutamine, 10% fetal bovine serum, 50 IU/ml penicillin G and 50 mg/ml streptomycin in 25 cm2 plastic culture flasks (Corning, Corning, NY, USA) at 37°C, with 5% CO2. For differentiation, neuroblastoma cells were exposed to 10 μM all-trans retinoic acid (RA, Sigma, St. Louis, MO, USA) for 14 days. The medium was changed every second day.
Neonatal rat cortical neuron culture
Primary culture of neonatal rat cortical neurons was prepared as described previously. Neurons were obtained from the cerebral cortex of newborn Wistar rats and plated onto 35 mm Petri dishes coated with poly-d-lysine (Sigma). The culture medium consisted of DMEM (Gibco) containing 20% fetal bovine serum, 2.5 μg/ml insulin and 45 mM glucose. The percentage of fetal bovine serum was gradually reduced to 5%. The medium was changed twice a week.
Inhibition of exocytosis
Tetanus toxin (TeNT, Sigma), an exocytosis inhibitor, was used to block the transport of secretory vesicles to the plasma membrane. RA differentiated neuroblastoma cells and primary neurons were treated with 5 or 20 nM tetanus toxin (TeNT) respectively for 24 h.
Primary anti-Aβ1–42 antibodies (Chemicon, Temecula, CA, USA), and anti-Aβ1–40 antibodies[36, 37] (Chemicon, Temecula, CA, USA), were rabbit polyclonal, while anti-human-Rab8 (marker for TGN and Golgi-derived secretory vesicles, BD biosciences, Franklin Lakes, NJ, USA), anti-Rab9 (marker for TGN and late endosomes, Abcam, Cambridge, UK), anti-Rab5 (marker for early endosomes, Pharmingen, San Diego, CA, USA), anti- LAMP-2 (marker for lysosomes and late endosomes, Southern Biotechnology, Birmingham, AL, USA), anti-VAMP 2 (synaptobrevin/VAMP 2, marker for synaptic vesicles, Synaptic Systems, Göttingen, Germany), and anti-Rab3 (marker for synaptic vesicles, Synaptic Systems) antibodies were mouse monoclonal IgG. Secondary antibodies were Alexa Fluor 488-conjugated goat anti-rabbit IgG and Alexa Fluor 546-conjugated goat anti-mouse IgG (both from Molecular Probes, Eugene, OR, USA).
The anti-Aβ42 antibodies (Chemicon) are specific for C-termini of Aβ peptide, and they do not cross-react with full-length APP, APP C-terminal fragments (CTF), or with Aβ40. We have also tested the specificity of anti-Aβ40 and anti-Aβ42 antibodies doing double immunostaining for Aβ and APP in control neuroblastoma cells. The anti-APP antibodies (Zymed, mouse anti-APP, clone LN27) recognize epitope within the first 200 amino acids in the APP N-terminus and react with all three known APP proteins. There is no cross-reactivity between Aβ and APP.
For immunofluorescence microscopy, cells on coverslips were washed twice in phosphate-buffered saline (PBS) and fixed in 4% neutral phosphate-buffered formaldehyde for 20 min at room temperature, rinsed in PBS, permeabilized with 0.1% saponin in PBS containing 5% serum for 20 min and incubated with primary antibodies for either single or double immunofluorescence for 1 h, followed by rinsing in PBS and 1 h incubation with secondary antibodies. Dilutions were 1:100 and 1: 400 for primary and secondary antibodies, respectively. For double immunostaining, different primary or secondary antibodies were applied simultaneously. The experiments were repeated at least three times.
After washing in PBS and distilled water, the specimens were mounted in Vectashield containing DAPI (Vector Laboratories, H-1200) and inspected with an inverted confocal laser scanning microscope (LSM 510 META, Zeiss) using a 488 nm argon laser and 543 nm helium-neon laser. For colocalization assessment, optical sections were no thicker than 0.6 μM. We also performed Nikon Microphot-SA fluorescence microscopy using a standard FITC / Texas Red double band-pass filter. Images were taken with a Hamamatsu ORCA 100 color digital camera (Hamamatsu, Japan). Images were prepared with Adobe Photoshop 7.0 (Adobe System).
To study Aβ localization in relation with different subcellular compartments, we performed immunogold electron microscopy using antibodies for Aβ40 and Aβ42. Low amount of Aβ labeling was found in the endoplasmic reticulum, Golgi complexes, lysosomal compartment and also mitochondria, but it was particularly abundant in the cytosol, usually in the form of clusters (Zheng et al., unpublished results).
A large number of studies have explored the intracellular sites of Aβ production, mostly in AD models. Aβ42 and Aβ40 monomers have been previously demonstrated in ER[6–8], TGN and post-TGN secretory vesicles, mitochondria, endosomes, lysosomes, multivesicular bodies (MVB), and cytosol[12, 45–47]. However, little is known about intracellular localization of Aβ in normal conditions, when Aβ is not overproduced.
In this study, we demonstrated that in differentiated neuroblastoma cells cultured under normal in vitro conditions, only little Aβ (including Aβ42 and Aβ40) showed colocalization with organelles such as TGN, Golgi-derived vesicles, early and late endosomes, lysosomes, or exocytotic vesicles, while the greater part of Aβ was located in the cytosol or in undetermined compartments.
The absence of major Aβ immunoreactivity in these cellular compartments, in which it was found in AD, as well as in cellular and in vivo AD models, suggests that, under normal conditions, this peptide is either relocated, or degraded, or secreted extracellularly. The fact that lysosomes showed little Aβ immunoreactivity would suggest that cells are able to perform a rapid proteolytic digestion of this peptide under normal biological conditions. In support of this hypothesis, we have previously shown that inhibition of lysosomal enzymes induces Aβ accumulation within the lysosomal compartment.
In addition, we have found that inhibition of exocytosis by TeNT induced a general increase of intracellular Aβ, both intra- and extralysosomal. As we previously reported, the intralysosomal Aβ accumulation can be mediated by enhanced Aβ autophagy. It is also possible that inhibition of exocytosis results in Aβ accumulation along the secretory pathway, including ER, Golgi apparatus, transport visicles and secretory vesicles.
Although under normal conditions late endosomes and lysosomes seem to be free of Aβ, this is not the case for AD neurons, in which Aβ has been demonstrated intralysosomally[10, 27, 28]. It is not clear what causes these changes and how Aβ relocation to lysosomes contributes to the pathogenesis of AD. One possible explanation is that oxidative stress might enhance autophagy, leading to intralysosomal Aβ accumulation, consequent lysosomal membrane damage and release of lysosomal enzymes to the cytosol, culminating in apoptosis[29, 30].
In AD, Aβ has been shown to accumulate within lysosomes, apparently promoting neuronal death through lysosomal destabilization[22, 25, 49]. As we previously demonstrated, intralysosomal Aβ accumulation can be triggered by oxidative stress and consequent activation of macroautophagy[29, 30]. On the other hand, Aβ has been shown to induce oxidant-mediated autophagic cell death in cultured cells, while antioxidants can protect cells from Aβ-mediated oxidative damage.
The fact that in the majority of AD cases there is no consistent overproduction of Aβ suggests that deficits in its degradation could lie behind the pathogenesis of the disease. On the other hand, intracellular accumulation of Aβ is proposed to compromise normal neuronal function in AD. Our findings demonstrate that, under normal conditions, intracellular Aβ (including Aβ42 and Aβ40) 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).
Amyloid Precursor Protein
Lysosomal Associated Membrane Protein-2
Mannose 6-phosphate Receptors
Trans Golgi network.
This work was supported by the Gustav V and Queen Victoria Foundation (JM), County Council of Östergötland (JM, LZ, MH), Stiftelsen Olle Engkvist Byggmästare (LZ), Stiftelsen för Gamla Tjänarinnor (LZ, AC-M), Loo and Hans Ostermans foundation (LZ), Gun och Bertil Stohnes Stiftelse (LZ, AC-M), Lions Forskningsfond (LZ), Svenska Lundbeckstiftelsen (LZ), Karolinska Institute Fund for Geriatric Research (AC-M), Alice och Knut Wallenberg Stiftelse (AC-M), Swedish Alzheimer Foundation (MH) and The Swedish Brain Power (AC-M).
- Masters CL, Beyreuther K: Pathways to the discovery of the Abeta amyloid of Alzheimer's disease. J Alzheimers Dis 2006, 9(3 Suppl):155-161.PubMedGoogle Scholar
- Selkoe DJ: The genetics and molecular pathology of Alzheimer's disease: roles of amyloid and the presenilins. Neurol Clin 2000, 18(4):903-922. 10.1016/S0733-8619(05)70232-2View ArticlePubMedGoogle Scholar
- Selkoe DJ: Alzheimer's disease: genes, proteins, and therapy. Physiol Rev 2001, 81(2):741-766.PubMedGoogle Scholar
- Sisodia SS: Beta-amyloid precursor protein cleavage by a membrane-bound protease. Proc Natl Acad Sci USA 1992, 89(13):6075-6079. 10.1073/pnas.89.13.6075PubMed CentralView ArticlePubMedGoogle Scholar
- Rogaeva E, et al.: The neuronal sortilin-related receptor SORL1 is genetically associated with Alzheimer disease. Nat Genet 2007, 39(2):168-177. 10.1038/ng1943PubMed CentralView ArticlePubMedGoogle Scholar
- Cook DG, et al.: Alzheimer's A beta(1–42) is generated in the endoplasmic reticulum/intermediate compartment of NT2N cells. Nat Med 1997, 3(9):1021-1023. 10.1038/nm0997-1021View ArticlePubMedGoogle Scholar
- Hartmann T, et al.: Distinct sites of intracellular production for Alzheimer's disease A beta40/42 amyloid peptides. Nat Med 1997, 3(9):1016-1020. 10.1038/nm0997-1016View ArticlePubMedGoogle Scholar
- Greenfield JP, et al.: Endoplasmic reticulum and trans-Golgi network generate distinct populations of Alzheimer beta-amyloid peptides. Proc Natl Acad Sci USA 1999, 96(2):742-747. 10.1073/pnas.96.2.742PubMed CentralView ArticlePubMedGoogle Scholar
- LaFerla FM, Green KN, Oddo S: Intracellular amyloid-beta in Alzheimer's disease. Nat Rev Neurosci 2007, 8(7):499-509. 10.1038/nrn2168View ArticlePubMedGoogle Scholar
- Yu WH, et al.: Macroautophagy–a novel Beta-amyloid peptide-generating pathway activated in Alzheimer's disease. J Cell Biol 2005, 171(1):87-98. 10.1083/jcb.200505082PubMed CentralView ArticlePubMedGoogle Scholar
- Serge G, et al.: Prevention strategies for Alzheimer¿s disease. Translational Neurodegeneration 2012., 1(13): 10.1186/2047-9158-1-13
- Gouras GK, et al.: Intraneuronal Abeta42 accumulation in human brain. Am J Pathol 2000, 156(1):15-20. 10.1016/S0002-9440(10)64700-1PubMed CentralView ArticlePubMedGoogle Scholar
- Naslund J, et al.: Correlation between elevated levels of amyloid beta-peptide in the brain and cognitive decline. JAMA 2000, 283(12):1571-1577. 10.1001/jama.283.12.1571View ArticlePubMedGoogle Scholar
- Gouras GK, et al.: Intraneuronal beta-amyloid accumulation and synapse pathology in Alzheimer's disease. Acta Neuropathol 2010, 119(5):523-541. 10.1007/s00401-010-0679-9PubMed CentralView ArticlePubMedGoogle Scholar
- D'Andrea MR, et al.: Evidence that neurones accumulating amyloid can undergo lysis to form amyloid plaques in Alzheimer's disease. Histopathology 2001, 38(2):120-134. 10.1046/j.1365-2559.2001.01082.xView ArticlePubMedGoogle Scholar
- Wirths O, et al.: Intraneuronal Abeta accumulation precedes plaque formation in beta-amyloid precursor protein and presenilin-1 double-transgenic mice. Neurosci Lett 2001, 306(1–2):116-120.View ArticlePubMedGoogle Scholar
- Takahashi RH, et al.: Intraneuronal Alzheimer abeta42 accumulates in multivesicular bodies and is associated with synaptic pathology. Am J Pathol 2002, 161(5):1869-1879. 10.1016/S0002-9440(10)64463-XPubMed CentralView ArticlePubMedGoogle Scholar
- Gandy S, et al.: Days to criterion as an indicator of toxicity associated with human Alzheimer amyloid-beta oligomers. Ann Neurol 2010, 68(2):220-230.PubMed CentralPubMedGoogle Scholar
- Knobloch M, et al.: Intracellular Abeta and cognitive deficits precede beta-amyloid deposition in transgenic arcAbeta mice. Neurobiol Aging 2007, 28(9):1297-306. 10.1016/j.neurobiolaging.2006.06.019View ArticlePubMedGoogle Scholar
- Tampellini D, et al.: Effects of synaptic modulation on beta-amyloid, synaptophysin, and memory performance in Alzheimer's disease transgenic mice. J Neurosci 2010, 30(43):14299-14304. 10.1523/JNEUROSCI.3383-10.2010PubMed CentralView ArticlePubMedGoogle Scholar
- Tampellini D, et al.: Impaired beta-Amyloid Secretion in Alzheimer's Disease Pathogenesis. J Neurosci 2011, 31(43):15384-15390. 10.1523/JNEUROSCI.2986-11.2011PubMed CentralView ArticlePubMedGoogle Scholar
- Nixon RA, Cataldo AM, Mathews PM: The endosomal-lysosomal system of neurons in Alzheimer's disease pathogenesis: a review. Neurochem Res 2000, 25(9–10):1161-1172.View ArticlePubMedGoogle Scholar
- Yu WH, et al.: Autophagic vacuoles are enriched in amyloid precursor protein-secretase activities: implications for beta-amyloid peptide over-production and localization in Alzheimer's disease. Int J Biochem Cell Biol 2004, 36(12):2531-2540. 10.1016/j.biocel.2004.05.010View ArticlePubMedGoogle Scholar
- Adamec E, et al.: Up-regulation of the lysosomal system in experimental models of neuronal injury: implications for Alzheimer's disease. Neurosci 2000, 100(3):663-675. 10.1016/S0306-4522(00)00281-5View ArticleGoogle Scholar
- Yang AJ, et al.: Loss of endosomal/lysosomal membrane impermeability is an early event in amyloid Abeta1-42 pathogenesis. J Neurosci Res 1998, 52(6):691-698. 10.1002/(SICI)1097-4547(19980615)52:6<691::AID-JNR8>3.0.CO;2-3View ArticlePubMedGoogle Scholar
- Liu J, et al.: Predominant release of lysosomal enzymes by newborn rat microglia after LPS treatment revealed by proteomic studies. J Proteome Res 2008, 7(5):2033-2049. 10.1021/pr7007779View ArticlePubMedGoogle Scholar
- Cataldo AM, et al.: Abeta localization in abnormal endosomes: association with earliest Abeta elevations in AD and Down syndrome. Neurobiol Aging 2004, 25(10):1263-1272. 10.1016/j.neurobiolaging.2004.02.027View ArticlePubMedGoogle Scholar
- Langui D, et al.: Subcellular topography of neuronal Abeta peptide in APPxPS1 transgenic mice. Am J Pathol 2004, 165(5):1465-1477. 10.1016/S0002-9440(10)63405-0PubMed CentralView ArticlePubMedGoogle Scholar
- Zheng L, et al.: Autophagy of amyloid beta-protein in differentiated neuroblastoma cells exposed to oxidative stress. Neurosci Lett 2006, 394(3):184-189. 10.1016/j.neulet.2005.10.035View ArticlePubMedGoogle Scholar
- Zheng L, et al.: Oxidative stress induces macroautophagy of amyloid beta-protein and ensuing apoptosis. Free Radic Biol Med 2009, 46(3):422-429. 10.1016/j.freeradbiomed.2008.10.043View ArticlePubMedGoogle Scholar
- Zheng L, Marcusson J, Terman A: Oxidative stress and Alzheimer disease: the autophagy connection? Autophagy 2006, 2(2):143-145.View ArticlePubMedGoogle Scholar
- Zheng L, et al.: Oxidative stress induces intralysosomal accumulation of Alzheimer amyloid beta-protein in cultured neuroblastoma cells. Ann N Y Acad Sci 2006, 1067: 248-251. 10.1196/annals.1354.032View ArticlePubMedGoogle Scholar
- Eva C, et al.: Primary cultures of corticostriatal cells from newborn rats: a model to study muscarinic receptor subtypes regulation and function. J Mol Neurosci 1990, 2(3):143-153. 10.1007/BF02896839View ArticlePubMedGoogle Scholar
- Verderio C, et al.: Tetanus toxin blocks the exocytosis of synaptic vesicles clustered at synapses but not of synaptic vesicles in isolated axons. J Neurosci 1999, 19(16):6723-6732.PubMedGoogle Scholar
- Kamal A, et al.: Kinesin-mediated axonal transport of a membrane compartment containing beta-secretase and presenilin-1 requires APP. Nature 2001, 414(6864):643-648. 10.1038/414643aView ArticlePubMedGoogle Scholar
- Yankner BA, et al.: Neurotoxicity of a fragment of the amyloid precursor associated with Alzheimer's disease. Science 1989, 245(4916):417-420. 10.1126/science.2474201View ArticlePubMedGoogle Scholar
- Kang J, et al.: The precursor of Alzheimer's disease amyloid A4 protein resembles a cell-surface receptor. Nature 1987, 325(6106):733-736. 10.1038/325733a0View ArticlePubMedGoogle Scholar
- Grigoriev I, et al.: Rab6, Rab8, and MICAL3 cooperate in controlling docking and fusion of exocytotic carriers. Curr Biol 2011, 21(11):967-974. 10.1016/j.cub.2011.04.030View ArticlePubMedGoogle Scholar
- Diaz E, Schimmoller F, Pfeffer SR: A novel Rab9 effector required for endosome-to-TGN transport. J Cell Biol 1997, 138(2):283-290. 10.1083/jcb.138.2.283PubMed CentralView ArticlePubMedGoogle Scholar
- Gouras GK, Almeida CG, Takahashi RH: Intraneuronal Abeta accumulation and origin of plaques in Alzheimer's disease. Neurobiol Aging 2005, 26(9):1235-1244. 10.1016/j.neurobiolaging.2005.05.022View ArticlePubMedGoogle Scholar
- Xu H, et al.: Generation of Alzheimer beta-amyloid protein in the trans-Golgi network in the apparent absence of vesicle formation. Proc Natl Acad Sci USA 1997, 94(8):3748-3752. 10.1073/pnas.94.8.3748PubMed CentralView ArticlePubMedGoogle Scholar
- Hansson Petersen CA, et al.: The amyloid beta-peptide is imported into mitochondria via the TOM import machinery and localized to mitochondrial cristae. Proc Natl Acad Sci USA 2008, 105(35):13145-13150. 10.1073/pnas.0806192105PubMed CentralView ArticlePubMedGoogle Scholar
- Pasternak SH, Callahan JW, Mahuran DJ: The role of the endosomal/lysosomal system in amyloid-beta production and the pathophysiology of Alzheimer's disease: reexamining the spatial paradox from a lysosomal perspective. J Alzheimers Dis 2004, 6(1):53-65.PubMedGoogle Scholar
- Takahashi RH, et al.: Oligomerization of Alzheimer's beta-amyloid within processes and synapses of cultured neurons and brain. J Neurosci 2004, 24(14):3592-3599. 10.1523/JNEUROSCI.5167-03.2004View ArticlePubMedGoogle Scholar
- Billings LM, et al.: Intraneuronal Abeta causes the onset of early Alzheimer's disease-related cognitive deficits in transgenic mice. Neuron 2005, 45(5):675-688. 10.1016/j.neuron.2005.01.040View ArticlePubMedGoogle Scholar
- Buckig A, et al.: Cytosolic and nuclear aggregation of the amyloid beta-peptide following its expression in the endoplasmic reticulum. Histochem Cell Biol 2002, 118(5):353-360. 10.1007/s00418-002-0459-2View ArticlePubMedGoogle Scholar
- Lee EK, et al.: Cytosolic amyloid-beta peptide 42 escaping from degradation induces cell death. Biochem Biophys Res Commun 2006, 344(2):471-477. 10.1016/j.bbrc.2006.03.166View ArticlePubMedGoogle Scholar
- Maxfield FR, Wustner D: Intracellular cholesterol transport. J Clin Invest 2002, 110(7):891-898.PubMed CentralView ArticlePubMedGoogle Scholar
- Ditaranto K, Tekirian TL, Yang AJ: Lysosomal membrane damage in soluble Abeta-mediated cell death in Alzheimer's disease. Neurobiol Dis 2001, 8(1):19-31. 10.1006/nbdi.2000.0364View ArticlePubMedGoogle Scholar
- Wang H, et al.: Amyloid-beta1-42 induces reactive oxygen species-mediated autophagic cell death in U87 and SH-SY5Y cells. J Alzheimers Dis 2010, 21(2):597-610.PubMedGoogle Scholar
- Ma G, Chen S: Diazoxide and N omega-nitro-L-arginine counteracted A beta 1-42-induced cytotoxicity. Neuroreport 2004, 15(11):1813-1817. 10.1097/01.wnr.0000135694.89237.3dView ArticlePubMedGoogle Scholar
- Tampellini D, Gouras GK: Synapses, synaptic activity and intraneuronal abeta in Alzheimer's disease. Front Aging Neurosci 2010., 2(13): 10.3389/fnagi.2010.00013
- Cirrito JR, et al.: Synaptic activity regulates interstitial fluid amyloid-beta levels in vivo. Neuron 2005, 48(6):913-922. 10.1016/j.neuron.2005.10.028View ArticlePubMedGoogle Scholar
- Shengdi Chen JCZ: Translational Neurodegeneration, a platform to share knowledge and experience in translational study of neurodegenerative diseases. Translational Neurodegeneration 2012., 1(1): 10.1186/2047-9158-1-1
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.