Abeta localization in abnormal endosomes: association with earliest Abeta elevations in AD and Down syndrome
ABSTRACT 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.
- SourceAvailable from: Jonathan D Geiger
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- "BACE-1, the rate-limiting enzyme in the production of Aβ, is located in endosomes (Rajendran et al., 2008; Shimizu et al., 2008; Vassar et al., 1999). Aβ is accumulated in endolysosomes of neurons from AD brain (Cataldo et al., 2004). Here, we showed that neurons treated with ApoB-containing LDL cholesterol exhibited increased Aβ production, increased accumulation of BACE-1 in endolysosomes, and increased BACE- 1 enzyme activity. "
ABSTRACT: AIMS: Elevated levels of circulating cholesterol are extrinsic factors contributing to the pathogenesis of sporadic Alzheimer's disease (AD). We showed previously that rabbits fed a cholesterol-enriched diet exhibited blood-brain barrier (BBB) dysfunction, increased accumulation of apolipoprotein B (ApoB) in brain neurons, and endolysosomes in brain had disturbed structures and functions. These effects were linked to increased amyloid beta (Aβ) production, increased tau-pathology, and disrupted synaptic integrity. Because pathological changes to endolysosomes represent a very early event in sporadic AD, we determined here the extent to which ApoB-containing LDL cholesterol altered the structure and function of endolysosomes and contributed to the development of AD-like pathology in primary cultured neurons. MAIN METHODS: Cholesterol distribution and endolysosome morphology were determined histologically. Endolysosome pH was measured ratio-metrically with LysoSensor dye. Endolysosome enzyme activity was measured for acid phosphatase, cathepsins B and D, and beta-site APP cleaving enzyme 1 (BACE-1). AD-like pathologies, including increased production of Aβ, increased tau-pathology, and disrupted synaptic integrity were determined using ELISA, immunoblotting, and immunostaining techniques. KEY FINDINGS: Treatment of neurons with ApoB-containing LDL cholesterol increased endolysosome accumulation of cholesterol, enlarged endolysosomes, and elevated endolysosome pH. In addition, ApoB-containing LDL cholesterol increased endolysosome accumulation of BACE-1, enhanced BACE-1 activity, increased Aβ levels, increased levels of phosphorylated tau, and decreased levels of synaptophysin. SIGNIFICANCE: Our findings suggest strongly that alterations in the structure and function of endolysosomes play a key role in the exhibition of pathological features of AD that result from neuronal exposure to ApoB-containing LDL cholesterol.Life sciences 05/2012; 91(23-24). DOI:10.1016/j.lfs.2012.04.039 · 2.30 Impact Factor
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- "Recent evidence increasingly implicates intracellular APP trafficking as a main mechanism regulating the access of APP to its secretases and thus Aβ generation . Moreover, endosome abnormalities and altered endocytic APP trafficking was reported to be involved in early steps of the disease pathogenesis    and upregulation of endocytosis leads to increased formation of Aβ  . Additionally, it has been recently shown that increased cholesterol levels initiate endosome enlargement and increased amyloidogenic processing of APP , supporting that alterations in cholesterol metabolism could initiate AD pathogenesis. "
ABSTRACT: Cholesterol accumulation in Niemann-Pick type C disease (NPC) causes increased levels of the amyloid-precursor-protein C-terminal fragments (APP-CTFs) and intracellular amyloid-β peptide (Aβ), the two central molecules in Alzheimer's disease (AD) pathogenesis. We previously reported that cholesterol accumulation in NPC-cells leads to cholesterol-dependent increased APP processing by β-secretase (BACE1) and decreased APP expression at the cell surface (Malnar et al. Biochim Biophys Acta. 1802 (2010) 682-691.). We hypothesized that increased formation of APP-CTFs and Aβ in NPC disease is due to cholesterol-mediated altered endocytic trafficking of APP and/or BACE1. Here, we show that APP endocytosis is prerequisite for enhanced Aβ levels in NPC-cells. Moreover, we observed that NPC cells show cholesterol dependent sequestration and colocalization of APP and BACE1 within enlarged early/recycling endosomes which can lead to increased β-secretase processing of APP. We demonstrated that increased endocytic localization of APP in NPC-cells is likely due to both its increased internalization and its decreased recycling to the cell surface. Our findings suggest that increased cholesterol levels, such as in NPC disease and sporadic AD, may be the upstream effector that drives amyloidogenic APP processing characteristic for Alzheimer's disease by altering endocytic trafficking of APP and BACE1.Biochimica et Biophysica Acta 04/2012; 1822(8):1270-83. DOI:10.1016/j.bbadis.2012.04.002 · 4.66 Impact Factor
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- "Targeting g-secretase for treatment Although there is a large body of supporting evidence that Ab40/42 contributes significantly to neuronal degeneration in AD, the role of Ab40/42 in impacting retrograde axonal signaling of NGF is much less clear. Yet Ab40/42 has been found to be present in intraneuronal endosomes (Cataldo et al., 2004). Significant efforts have been invested in developing inhibitors that target the secretases that cleave App and give rise to Ab40/42, that is, the b-or g-secretase (Anderson et al., 2005; Evin et al., 2010; Kounnas et al., 2010; Pasternak et al., 2003; Sabo et al., 1999; Shinohara et al., 2010; Van Nostrand et al., 1992a,b; Vetrivel et al., 2004, 2011; Zhang et al., 2006). "
ABSTRACT: This review describes recent discoveries in neurobiology of Down syndrome (DS) achieved with use of mouse genetic models and provides an overview of experimental approaches aimed at development of pharmacological restoration of cognitive function in people with this developmental disorder. Changes in structure and function of synaptic connections within the hippocampal formation of DS model mice, as well as alterations in innervations of the hippocampus by noradrenergic and cholinergic neuromodulatory systems, provided important clues for potential pharmacological treatments of cognitive disabilities in DS. Possible molecular and cellular mechanisms underlying this genetic disorder have been addressed. We discuss novel mechanisms engaging misprocessing of amyloid precursor protein (App) and other proteins, through their affect on axonal transport and endosomal dysfunction, to "Alzheimer-type" neurodegenerative processes that affect cognition later in life. In conclusion, a number of therapeutic strategies have been defined that may restore cognitive function in mouse models of DS. In the juvenile and young animals, these strategists focus on restoration of synaptic plasticity, rate of adult neurogenesis, and functions of the neuromodulatory subcortical systems. Later in life, the major focus is on recuperation of misprocessed App and related proteins. It is hoped that the identification of an increasing number of potential targets for pharmacotherapy of cognitive deficits in DS will add to the momentum for creating and completing clinical trials.Progress in brain research 01/2012; 197:199-221. DOI:10.1016/B978-0-444-54299-1.00010-8 · 5.10 Impact Factor