Amyloid precursor protein and alpha synuclein translation, implications for iron and inflammation in neurodegenerative diseases

AbstractAlzheimer’s disease (AD) is among the most prevalent neurodegenerative diseases, with brain pathology defined by extracellular amyloid beta deposits and intracellular tau aggregates. To aid in research efforts to improve understanding of this disease, transgenic murine models have been developed that replicate aspects of AD pathology. Familial AD is associated with mutations in the amyloid precursor protein and in the presenilins (associated with amyloidosis); transgenic amyloid models feature one or more of these mutant genes. Recent advances in seeding methods provide a means to alter the morphology of resultant amyloid deposits and the age that pathology develops. In this review, we discuss the variety of factors that influence the seeding of amyloid beta pathology, including the source of seed, the time interval after seeding, the nature of the transgenic host, and the preparation of the seeding inoculum.

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Pulsed Telecommunication Signals of Non-ionizing Radiation Affect Amyloid Precursor Protein and α-Synuclein Metabolism in Non-neural Human Cells

10.20944/preprints202008.0587.v1 ◽

2020 ◽

Author(s):

AIKATERINA STEFI ◽

KATERINA SKOUROLIAKOU ◽

LUKAS MARGARITIS ◽

DIDO VASSILACOPOULOU

Keyword(s):

Amyloid Precursor Protein ◽

Alpha Synuclein ◽

Human Cells ◽

Precursor Protein ◽

Whole Body ◽

Neural Cells ◽

Telecommunications Network ◽

App Metabolism ◽

Living Organisms

The expanding use of devices emitting Pulsed Telecommunication Signals (PTS) has launched a serious debate over the possible effects of electromagnetic radiation (EMR) on living organisms. Our previous work has indicated that PTS exposure alters Amyloid Precursor Protein (APP) and alpha-synuclein (α-syn) metabolism in human cells of neural origin, providing a possible connection between exposure and neurodegeneration. This investigation aimed to reveal, in vitro in human non-neural cells (HEK293), the aftermath of the same exposure on the processing of APP and α-syn. Data presented here, indicate changes in APP metabolism, acquisition of different cellular topologies of the newly generated APP fragments, changes in monomeric α-syn accumulation and multimerization, indicating that APP and α-syn processing is possibly altered in the periphery by EMR. These effects are accompanied by a substantial increase in the levels of Reactive Oxygen Species (ROS). Further investigation is required in order to provide insights into the interaction of PTS with non-neural cells affecting the peripheral systemic functional stability. This is necessary because nowadays whole body human exposure from various EMR sources is a fact in normal life with the valid estimation that they may be increased in view of the forthcoming 5G telecommunications network implementation.

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Transmissible Endosomal Intoxication: A Balance between Exosomes and Lysosomes at the Basis of Intercellular Amyloid Propagation

Biomedicines ◽

10.3390/biomedicines8080272 ◽

2020 ◽

Vol 8 (8) ◽

pp. 272

Author(s):

Anaïs Bécot ◽

Charlotte Volgers ◽

Guillaume van Niel

Keyword(s):

Amyloid Precursor Protein ◽

Neurodegenerative Diseases ◽

Multivesicular Body ◽

Precursor Protein ◽

Aβ Peptides ◽

Amyloid Aβ ◽

Β Amyloid ◽

Novel Concept ◽

The Brain

In Alzheimer′s disease (AD), endolysosomal dysfunctions are amongst the earliest cellular features to appear. Each organelle of the endolysosomal system, from the multivesicular body (MVB) to the lysosome, contributes to the homeostasis of amyloid precursor protein (APP) cleavage products including β-amyloid (Aβ) peptides. Hence, this review will attempt to disentangle how changes in the endolysosomal system cumulate to the generation of toxic amyloid species and hamper their degradation. We highlight that the formation of MVBs and the generation of amyloid species are closely linked and describe how the molecular machineries acting at MVBs determine the generation and sorting of APP cleavage products towards their degradation or release in association with exosomes. In particular, we will focus on AD-related distortions of the endolysomal system that divert it from its degradative function to favour the release of exosomes and associated amyloid species. We propose here that such an imbalance transposed at the brain scale poses a novel concept of transmissible endosomal intoxication (TEI). This TEI would initiate a self-perpetuating transmission of endosomal dysfunction between cells that would support the propagation of amyloid species in neurodegenerative diseases.

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Amyloid Precursor Protein, Presenilins, and alpha -Synuclein: Molecular Pathogenesis and Pharmacological Applications in Alzheimer's Disease

Pharmacological Reviews ◽

10.1124/pr.54.3.469 ◽

2002 ◽

Vol 54 (3) ◽

pp. 469-525 ◽

Cited By ~ 317

Author(s):

Y.-H. Suh

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Amyloid Precursor Protein ◽

Alpha Synuclein ◽

Molecular Pathogenesis ◽

Precursor Protein

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2.317 Regulation of the iron-responsive proteins amyloid precursor protein and alpha-synuclein by green tea polyphenol (−)-epigallocatechin-3-gallate

Parkinsonism & Related Disorders ◽

10.1016/s1353-8020(08)70715-6 ◽

2007 ◽

Vol 13 ◽

pp. S126

Author(s):

L. Reznichenko ◽

T. Amit ◽

O. Weinreb ◽

M.B.H. Youdim ◽

S.A. Mandel

Keyword(s):

Amyloid Precursor Protein ◽

Green Tea ◽

Alpha Synuclein ◽

Precursor Protein ◽

Tea Polyphenol ◽

Green Tea Polyphenol

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2.021 Regulation of the iron-responsive proteins amyloid precursor protein and alpha-synuclein by green tea polyphenol (−)-epigallocatechin-3-gallate

Parkinsonism & Related Disorders ◽

10.1016/s1353-8020(08)70589-3 ◽

2007 ◽

Vol 13 ◽

pp. S91

Author(s):

L. Reznichenko ◽

T. Amit ◽

O. Weinreb ◽

M.B.H. Youdim ◽

S.A. Mandel

Keyword(s):

Amyloid Precursor Protein ◽

Green Tea ◽

Alpha Synuclein ◽

Precursor Protein ◽

Tea Polyphenol ◽

Green Tea Polyphenol

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Mitochondrial fission is a critical modulator of mutant APP-induced neural toxicity

10.1101/2020.05.10.087346 ◽

2020 ◽

Author(s):

Lauren Y. Shields ◽

Huihui Li ◽

Kevin Nguyen ◽

Hwajin Kim ◽

Zak Doric ◽

...

Keyword(s):

Amyloid Precursor Protein ◽

Neurodegenerative Diseases ◽

Learning And Memory ◽

Mitochondrial Fission ◽

Precursor Protein ◽

Cultured Neurons ◽

Potential Mechanism ◽

Normal Functions ◽

Associated Proteins ◽

Neural Toxicity

ABSTRACTAlterations in mitochondrial fission may contribute to the pathophysiology of several neurodegenerative diseases, including Alzheimer’s disease (AD). However, we understand very little about the normal functions of fission, or how fission disruption may interact with AD-associated proteins to modulate pathogenesis. Here we show that loss of the central mitochondrial fission protein dynamin-related 1 (Drp1) in CA1 and other forebrain neurons markedly worsens the learning and memory of mice expressing mutant human amyloid-precursor protein (hAPP) in neurons. In cultured neurons, Drp1KO and hAPP converge to produce mitochondrial Ca2+ (mitoCa2+) overload, despite decreasing mitochondria-associated ER membranes (MAMs) and cytosolic Ca2+. This mitoCa2+ overload occurs independently of ATP levels. These findings reveal a potential mechanism by which mitochondrial fission protects against hAPP-driven pathology.

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Memapsin 2, a drug target for Alzheimer's disease

Biochemical Society Symposium ◽

10.1042/bss0700213 ◽

2003 ◽

Vol 70 ◽

pp. 213-220 ◽

Cited By ~ 1

Author(s):

Gerald Koelsch ◽

Robert T. Turner ◽

Lin Hong ◽

Arun K. Ghosh ◽

Jordan Tang

Keyword(s):

Crystal Structure ◽

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Transition State ◽

Amyloid Precursor Protein ◽

Therapeutic Target ◽

Drug Target ◽

Aspartic Protease ◽

Precursor Protein ◽

Memapsin 2

Mempasin 2, a ϐ-secretase, is the membrane-anchored aspartic protease that initiates the cleavage of amyloid precursor protein leading to the production of ϐ-amyloid and the onset of Alzheimer's disease. Thus memapsin 2 is a major therapeutic target for the development of inhibitor drugs for the disease. Many biochemical tools, such as the specificity and crystal structure, have been established and have led to the design of potent and relatively small transition-state inhibitors. Although developing a clinically viable mempasin 2 inhibitor remains challenging, progress to date renders hope that memapsin 2 inhibitors may ultimately be useful for therapeutic reduction of ϐ-amyloid.

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