Aβ localization in abnormal endosomes: Association with earliest Aβ elevations in AD and Down syndrome

Mailman Research Center, McLean Hospital, 115 Mill Street, Belmont, MA 02478, USA.
Neurobiology of Aging (Impact Factor: 5.01). 11/2004; 25(10):1263-72. DOI: 10.1016/j.neurobiolaging.2004.02.027
Source: PubMed


Early endosomes are a major site of amyloid precursor protein (APP) processing and a convergence point for molecules of pathologic relevance to Alzheimer's disease (AD). Neuronal endosome enlargement, reflecting altered endocytic function, is a disease-specific response that develops years before the earliest stage of AD and Down syndrome (DS). We examined how endocytic dysfunction is related to Abeta accumulation and distribution in early stage AD and DS. We found by ELISA and immunocytochemistry that the appearance of enlarged endosomes coincided with an initial rise in soluble Abeta40 and Abeta42 peptides, which preceded amyloid deposition. Double-immunofluorescence using numerous Abeta antibodies showed that intracellular Abeta localized principally to rab5-positive endosomes in neurons from AD brains and was prominent in enlarged endosomes. Abeta was not detectable in neurons from normal controls and was diminished after amyloid deposition in neuropathologically confirmed AD. These studies support growing evidence that endosomal pathology contributes significantly to Abeta overproduction and accumulation in sporadic AD and in AD associated with DS and may signify earlier disease-relevant disturbances of the signaling functions of endosomes.

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    • "Interestingly, accumulation of intracellular Aβ was detected before the appearance of amyloid plaques in transgenic AD mice where it was associated with the onset of cognitive impairment (Billings et al., 2005; Knobloch et al., 2007). Also in patients with AD and Down's syndrome, intracellular Aβ was detected in post-mortem brains (Cataldo et al., 2004). Furthermore, this intracellularly generated Aβ found to be more potent in causing neuronal cell death than extracellular Aβ (Kienlen-Campard et al., 2002). "
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    • "A reduced expression of the autophagy-related protein Beclin-1, which is required for the early step of autophagosome formation [10], and co-localization of sequestosome 1/p62 (an adaptor protein with several functional domains to target polyubiquitinated protein cargo to autophagosomes), ubiquitin, and hyperphosphorylated tau in aggregates have been reported in the cortex and hippocampus of AD patients [11,12]. Furthermore, in familial AD, autophagosomes proliferated and the level of LC3-II (a marker of autophagosome) increased [13]. In addition, components required for the generation of Aβ (amyloid precursor protein (APP), presenilin 1 (PS1), nicastrin, and β-secretase) are found in autophagic vacuoles (AVs) [14]. "
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    ABSTRACT: Autophagy is a major pathway of protein and organelle degradation in the lysosome. Autophagy exists at basal constitutive level and can be induced as a defense mechanism under stress conditions. Molecular relationships between autophagy and inflammation at the periphery were recently evidenced, highlighting a role of autophagy in the regulation of inflammation. Impairment of autophagy (with accumulation of autophagic vacuoles) and substantial inflammation are found in neurodegenerative diseases such as Alzheimer's Disease (AD). However, the links between autophagy and inflammation in AD remain to be determined. Here, we examined the inflammatory reaction and autophagy in murine tri-cultures of neurons, astrocytes, and microglia. Tri-cultures were exposed to various inflammatory stresses (lipopolysaccharide (LPS), amyloid peptide (Abeta42) with or without cytokines) for 48 hours. Furthermore, the relationships between inflammation and autophagy were also analyzed in astrocyte- and microglia-enriched cultures. Data for multiple variable comparisons were analyzed by a one-way ANOVA followed by a Newman-keuls' test. Abeta42 induced a low inflammation without accumulation of acidic vesicles contrary to moderate or severe inflammation induced by LPS or the cytokine cocktail (IL-1beta, TNF-alpha, and IL-6) or IL-1beta alone which led to co-localization of p62 and LC3, two markers of autophagy, with acidic vesicles stained with Lyso-ID Red dye. Moreover, the study reveals a major role of IL-1beta in the induction of autophagy in tri-cultures in the presence or absence of Abeta42. However, the vulnerability of the autophagic process in purified microglia to IL-1beta was prevented by Abeta42. These findings show a close relationship between inflammation and autophagy, in particular a major role of IL-1beta in the induction of the microglial autophagy which could be the case in AD. New therapeutic strategies could target inflammasome and autophagy in microglia to maintain its role in the amyloid immunosurveillance.
    Journal of Neuroinflammation 12/2013; 10(1):151. DOI:10.1186/1742-2094-10-151 · 5.41 Impact Factor
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    • "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 [10], and lysosomes [28-30]. "
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    ABSTRACT: 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.
    Translational Neurodegeneration 09/2012; 1(1):19. DOI:10.1186/2047-9158-1-19
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