α2-Macroglobulin-Mediated Degradation of Amyloid β1–42: A Mechanism to Enhance Amyloid β Catabolism

doi:10.1006/exnr.2000.7569

Experimental Neurology

Volume 167, Issue 2, February 2001, Pages 385-392

Dedicated to Prof. G Kopperschläger on the occasion of his 65th birthday.

https://doi.org/10.1006/exnr.2000.7569 Get rights and content

Abstract

Peptides derived from proteolytic degradation of the amyloid precursor protein, e.g., amyloid β (Aβ), are considered to be central to the pathology of Alzheimer's disease (AD). Soluble Aβ is present in measurable concentrations in cerebrospinal fluid and blood. There are indications that soluble Aβ present in circulation can cross the blood–brain barrier via transcytosis mediated by brain capillary endothelial cells. It implies that Aβ originating from circulation may contribute to vascular and parenchymal Aβ deposition in AD. Enhancing of Aβ catabolism mediated by proteolytic degradation or receptor-mediated endocytosis could be a key mechanism to maintain low concentrations of soluble Aβ. To launch Aβ clearance we have exploited the Aβ-degrading activity of diverse α2-macroglobulin (α2-M)–proteinase complexes. Complexes with trypsin, α-chymotrypsin, and bromelain strongly degrade ¹²⁵I-Aβ1–42 whereas complexes with endogenous proteinases, e.g., plasmin and prostate-specific antigen, were not effective. Aβ degradation by the complexes was not inhibited by α1-antichymotrypsin and soybean trypsin inhibitor which normally would inactivate the free serine proteinases. A prerequisite for Aβ degradation is its binding to specific binding sites in α2-M that may direct Aβ to the active site of the caged proteinase. Ex vivo, enhanced degradation of ¹²⁵I-Aβ1–42 in blood could be achieved upon oral administration of high doses of proteinases to volunteers. These results suggest that up-regulation of Aβ catabolism could probably reduce the risk of developing AD by preventing Aβ accumulation in brain and vasculature.

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Amyloid beta (Aβ) is a peptide derived from proteolytic degradation of the amyloid precursor protein (APP). Aβ aggregation is critical in development of Alzheimer’s disease (AD) [172]. Though Aβ is normally generated in the brain, it can be produced by other tissues (e.g. gut) and transported via the circulatory system into the brain.
The blood brain barrier (BBB) is a neurovascular unit that protects the brain from peripheral insults, and plays a critical role in regulating cerebral homeostasis. Data have consistently demonstrated BBB inflammation as the hallmark of several central nervous system (CNS) diseases. Unfortunately, the mechanisms that trigger BBB inflammation in different CNS disorders are not fully understood. In particular, it is not known how the BBB changes from a protective barrier to a pathological one that underlies disruptive processes in the cerebral microenvironment. The constantly rising incidence of CNS diseases substantiates the need to investigate the mechanisms of BBB inflammation and search for novel frontiers in the treatment of these disorders. This review integrates recent data that suggest the molecular culprits of BBB inflammation in different CNS diseases. BBB inflammation in different CNS disorders is characterized by specific changes in the molecular architecture of the barrier, but also, share similar pathogenic signaling pathways. Due to their anti-inflammatory potential, phytochemicals may provide huge therapeutic benefits in BBB inflammation and drug development. A better understanding of the mechanisms of BBB inflammation holds promise for identifying potential targets for diagnostics and therapeutics of BBB disruption in CNS disorders.
Amyloid β-interacting partners in Alzheimer's disease: From accomplices to possible therapeutic targets
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α2-Macroglobulin is the specific ligand for LRP, and promotes Aβ clearance through LRP in cortical neurons (Chappell et al., 1992; Qiu et al., 1999). Interaction of Aβ with α2-macroglobulin protease complexes increases Aβ degradation, which may reduce the risk of AD development (Lauer et al., 2001). Notably, α2-macroglobulin is one of the confirmed late onset genes leading to an increased risk for AD (Blacker et al., 1998; Kovacs, 2000).
Alzheimer's disease (AD) is one of the most devastating neurodegenerative diseases in modern society because of insurmountable difficulties in early diagnosis and lack of therapeutic treatments. AD pathogenesis is tightly linked to the abnormal accumulation and aggregation of amyloid β (Aβ), seemingly the main causative factor of AD; however, intensive research on Aβ has not yet explained the complexity of AD pathogenesis. Consequently, the role of other supportive partners of Aβ have been elucidated and evaluated in the etiology of AD, and their potential molecular mechanisms have emerged as possible therapeutic targets. In this review, we compile information regarding Aβ-interacting partners in normal conditions and AD pathology, and analyze their etiological roles in diverse areas. Furthermore, we integrate this information into suggestions for probable clinical applications for AD diagnosis and therapeutics. We include Aβ-interacting partners localized to the cell surface and intracellular and extracellular compartments of different cell types ranging from the central nervous system to peripheral regions. Additionally, we expand the range of Aβ-interacting partners by including not only proteins, but also inorganic substances like metals, expecting that one of these partners may yield a critical breakthrough in the field of AD diagnostics and therapeutic drug development.
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Its actions also include antitumor properties, immunity modulation, enhanced wound healing, and cardiovascular and circulatory improvement (Hale, Greer, Trinh, & James, 2005; Maurer, 2001). In addition, the applicability of FBM in case of Alzheimer's disease patients in vivo has been proven to be promising (Lauer, Reichenbach, & Birkenmeier, 2001). Given several beneficial effects that pineapple possesses, the processing of its product is very crucial, targeting a maximum retention of its therapeutic value through FBM.
The stability of fruit bromelain (FBM) in pineapple pulp was studied within a high-pressure domain of 0.1–600 MPa/30–70 °C/1 s–30 min. The pulse effect was quantified as a function of pressure, temperature, pressure build-up and decompression times. A maximum of 60% reduction in FBM activity was obtained after a single pulse of 600 MPa/70 °C. Upon applying nth order model, the obtained reaction order (n) for thermal (0.1 MPa/30–70 °C) and high-pressure (100–600 MPa/30–70 °C) inactivation was 1.1 and 1.2, respectively. The inactivation rate constant (k) ranged from 1.2 to 45.0 × 10^− 3 Uⁿ ⁻ ¹ min^− 1. The activation energy was nonlinearly dependent on pressure (P); whereas, the activation volume was linearly related to temperature (T). The nonlinear dependence of k on P and T was modeled by an empirical equation. The D-values obtained from the empirical model appeared to be more realistic than those from the log-linear kinetics.
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Regular Articleα2-Macroglobulin-Mediated Degradation of Amyloid β1–42: A Mechanism to Enhance Amyloid β Catabolism

Abstract

Biochim. Biophys. Acta

J. Neuroimmunol.

Neurobiol. Dis.

Neurosci. Lett.

J. Urol.

Neurobiol. Dis.

J. Biol. Chem.

J. Biol. Chem.

J. Biol. Chem.

Brain Res.

Neurobiol. Dis.

Absorption of exogenous and endogenous proteolytic enzymes

Clin. Pharmacol. Ther.

Alpha-2 macroglobulin is genetically associated with Alzheimer disease

Nature Genet.

Transport of proteolytic enzymes across Caco-2 cell monolayers

Pharm. Res.

α2-Macroglobulin, a multifunctional binding protein with targeting characteristics

FASEB J.

Intestinal absorption of undegraded proteins in men: Presence of bromelain in plasma after oral intake

Am. J. Physiol.

The pathogenesis of senile plaques

J. Neuropathol. Exp. Neurol.

Alpha2-macroglobulin attenuates beta-amyloid peptide 1–40 fibril formation and associated neurotoxicity of cultured fetal rat cortical neurons

J. Neurochem.

Regular Article
α2-Macroglobulin-Mediated Degradation of Amyloid β1–42: A Mechanism to Enhance Amyloid β Catabolism