Gene expression and cellular content of cathepsin D in Alzheimer's disease brain: Evidence for early up-regulation of the endosomal-lysosomal system

McLean Hospital, Harvard Medical School, Belmont, Massachusetts 02178.
Neuron (Impact Factor: 15.05). 04/1995; 14(3):671-80. DOI: 10.1016/0896-6273(95)90324-0
Source: PubMed


In Alzheimer's disease brains, more than 90% of pyramidal neurons in lamina V and 70% in lamina III displayed 2- to 5-fold elevated levels of cathepsin D (Cat D) mRNA by in situ hybridization compared with neurologically normal controls. Most of these cells appeared histologically normal. The less vulnerable nonpyramidal neuron population in lamina IV had relatively normal message levels. Neuronal populations expressing more Cat D mRNA also displayed quantitatively increased Cat D immunoreactive protein. Cat D mRNA expression was only moderately increased in astrocytes. Degenerating neurons exhibited intense immunoreactivity but lowered Cat D mRNA levels. The upregulation of Cat D synthesis and accumulation of hydrolase-laden lysosomes indicate an early activation of the endosomal-lysosomal system in vulnerable neuronal populations, possibly reflecting early regenerative or repair processes. These abnormalities also represent a basis for altered regulation of amyloid precursor protein processing.

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    • "Many neurological diseases are characterized by mutations of proteins involved in endosomal/lysosomal transport, and deregulation of endosomal trafficking is a common feature in AD. Evidence have been reported demonstrating an increase of lysosomal glycohydrolases activity in the brain and also in peripheral tissues of AD patients (Adamec et al., 2000; Cataldo et al., 1996, 1995; Emiliani et al., 2003; Mathews et al., 2002; Nixon et al., 2001). A critical role of lysosomal system alteration in neurodegeneration is supported by studies of primary lysosomal storage disorders (LSDs) (Tancini et al. 2010). "
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    ABSTRACT: A critical role of endosomal-lysosomal system alteration in neurodegeneration is supported by several studies. Dysfunction of the lysosomal compartment is a common feature also in Alzheimer’s disease. Altered expression of lysosomal glycohydrolases has been demonstrated not only in the brain and peripheral tissues of Alzheimer’s disease patients, but also in presymptomatic subjects before degenerative phenomenon becomes evident. Moreover, the presence of glycohydrolases associated to the plasma membrane have been widely demonstrated and their alteration in pathological conditions has been documented. In particular, lipid microdomains-associated glycohydrolases can be functional to the maintenance of the proper glycosphingolipids pattern, especially at cell surface level, where they are crucial for the function of cell types such as neurons. In this study we investigated the localization of β-hexosaminidase and β-galactosidase glycohydrolases, both involved in step by step degradation of the GM1 to GM3 gangliosides, in lipid microdomains from the cortex of both an early and advanced TgCRND8 mouse model of Alzheimer’s disease. Throughout immunoprecipitation experiments of purified cortical lipid microdomains, we demonstrated for the first time that β-hexosaminidase and β-galactosidase are associated with post-synaptic vesicles and that their activities are increased at both the early and the advanced stage of Alzheimer’s disease. The early increase of lipid microdomain-associated β-hexosaminidase and β-galactosidase activities could have relevant implications for the pathophysiology of the disease since their possible pharmacological manipulation could shed light on new reliable targets and biological markers of Alzheimer’s disease.
    The International Journal of Biochemistry & Cell Biology 11/2014; 58. DOI:10.1016/j.biocel.2014.11.001 · 4.05 Impact Factor
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    • "This leads to an increased demand for hydrolases in EE of neurons within affected regions of AD brains, which may activate alternative mechanisms of delivery to this compartment. Furthermore, in AD and similar conditions, some other specific pathological phenomena involving the endosomal–lysosomal system have been observed, such as the persistence of acid hydrolase deposits in the extracellular space, coming from degenerating neurons (reviewed in Cataldo et al., 1995). "
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    ABSTRACT: Lysosomal storage disorders (LSDs) are a group of rare genetic diseases, generally caused by a deficiency of specific lysosomal enzymes, which results in abnormal accumulation of undegraded substrates. The first clinical reports describing what were later shown to be LSDs were published more than a hundred years ago. In general, the history and pathophysiology of LSDs have impacted on our current knowledge of lysosomal biology. Classically, depending on the nature of the substrates, LSDs can be divided into different subgroups. The mucopolysaccharidoses (MPSs) are those caused by impaired degradation of glycosaminoglycans (GAGs). Amongst LSDs, the MPSs are a major group of pathologies with crucial historical relevance, since their study has revealed important biological pathways and highlighted interconnecting pathological cascades which are still being unveiled nowadays. Here we review the major historical discoveries in the field of LSDs and their impact on basic cellular knowledge and practical applications. Attention will be focused on the MPSs, with occasional references to other LSDs. We will show as studies on the metabolic basis of this group of diseases have increased our knowledge of the complex degradative pathways associated with the lysosome and established the basis to the development of specific therapeutic approaches aiming at correcting or, at least ameliorating their associated phenotypes.
    Gene 09/2014; 555(1). DOI:10.1016/j.gene.2014.09.054 · 2.14 Impact Factor
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    • "Some of the enzymes such as cathepsins B and D are also known to affect cell viability following their release into the cytosol [28], [60]–[63]. Evidence suggests that cathepsins may be involved in the generation of Aβ peptides and their levels/expressions are increased in the vulnerable neurons as well as plasma of AD patients [33]–[35], [64]–[67]. Inhibitors of cathepsin B or deletion of the gene have been shown to reduce Aβ burden in mutant APP transgenic mice [68], [69]. Interestingly, overexpression of the IGF-II receptor shows a decreased expression of Ctsb and Ctsd transcripts and pro-forms of the enzymes, while the levels of mature enzymes are increased possibly due to efficient M6P-dependent trafficking and proteolytic conversion of the pro-forms to active enzymes in endosomes and lysosomes [70]. "
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    ABSTRACT: Alzheimer's disease (AD) is the most common type of senile dementia affecting elderly people. The processing of amyloid precursor protein (APP) leading to the generation of β-amyloid (Aβ) peptide contributes to neurodegeneration and development of AD pathology. The endocytic trafficking pathway, which comprises of the endosomes and lysosomes, acts as an important site for Aβ generation, and endocytic dysfunction has been linked to increased Aβ production and loss of neurons in AD brains. Since insulin-like growth factor-II (IGF-II) receptor plays a critical role in the transport of lysosomal enzymes from the trans-Golgi network to endosomes, it is likely that the receptor may have a role in regulating Aβ metabolism in AD pathology. However, very little is known on how altered levels of the IGF-II receptor can influence the expression/function of various molecules involved in AD pathology. To address this issue, we evaluated the expression profiles of 87 selected genes related to AD pathology in mouse fibroblast MS cells that are deficient in murine IGF-II receptor and corresponding MS9II cells overexpressing ∼500 times the human IGF-II receptors. Our results reveal that an elevation in IGF-II receptor levels alters the expression profiles of a number of genes including APP as well as enzymes regulating Aβ production, degradation and clearance mechanisms. Additionally, it influences the expression of various lysosomal enzymes and protein kinases that are involved in Aβ toxicity. IGF-II receptor overexpression also alters expression of several genes involved in intracellular signalling as well as cholesterol metabolism, which play a critical role in AD pathology. The altered gene profiles observed in this study closely match with the corresponding protein levels, with a few exceptions. These results, taken together, suggest that an elevation in IGF-II receptor levels can influence the expression profiles of transcripts as well as proteins that are involved in AD pathogenesis.
    PLoS ONE 05/2014; 9(5):e98057. DOI:10.1371/journal.pone.0098057 · 3.23 Impact Factor
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