The Genetics of Alzheimer’s Disease

Barber, Robert C.

doi:10.6064/2012/246210

Cited by 85 publications

(85 citation statements)

References 158 publications

(178 reference statements)

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“…The amyloid protein precursor is processed and can generate numerous fragments. Cleavage by alpha‐secretase creates fragments not related to senile plaques, whereas cleavage by beta‐ and gamma‐secretase creates β‐amyloid, a neurotoxic fragment . β‐Amyloid proteins have the ability to aggregate in the extracellular part of neurons, forming amyloid fibers that are the main components of senile plaques, which are directly related to neuronal degeneration in Alzheimer's patients .…”

Section: Discussionmentioning

confidence: 99%

MALDI‐imaging analyses of honeybee brains exposed to a neonicotinoid insecticide

Catae

Menegasso

Pratavieira

et al. 2018

Pest Management Science

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BACKGROUND: Toxicological studies evaluating the possible harmful effects of pesticides on bees are important and allow the emergence of protection and pollinator conservation strategies. This study aimed to evaluate the effects of exposure to a sublethal concentration of imidacloprid (LC 50/100 : 0.014651 ng imidacloprid L −1 diet) on the distribution of certain proteins identified in the brain of Apis mellifera worker bees using a MALDI-imaging approach. This technique enables proteomic analysis of tissues in situ by monitoring the spatiotemporal dynamics of the biochemical processes occurring at a specific time in specific brain neuropils. For this purpose, foraging bees were exposed to an 8-day diet containing a sublethal concentration of imidacloprid corresponding to the LC 50/100 . Bees were collected on day 8 of exposure, and their brains analyzed using protein density maps. RESULTS:The results showed that exposure to imidacloprid led to a series of biochemical changes, including alterations in synapse regulation, apoptosis regulation and oxidative stress, which may adversely impair the physiology of these colony bees. CONCLUSION: Worker bee contact with even tiny amounts of imidacloprid had potent effects leading to the overexpression of a series of proteins related to important cellular processes that were possibly damaged by the insecticide.

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Section: Discussionmentioning

confidence: 99%

MALDI‐imaging analyses of honeybee brains exposed to a neonicotinoid insecticide

Catae

Menegasso

Pratavieira

et al. 2018

Pest Management Science

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“…The scenario resulting in a CTF of conventionally encoded polypeptide as the outcome of mRNA amplification can be illustrated with the case of beta-amyloid overproduction in sporadic Alzheimer's disease. Beta amyloid, Aβ, the peptide associated with and, when overproduced, widely believed to have a pivotal early role in the etiology of Alzheimer's disease (AD), is normally generated by proteolytic cleavages of a much larger molecule, β amyloid precursor protein, βAPP (28)(29)(30)(31)(32)(33)(34)(35)(36). Two sequential cleavages of βAPP are involved in the production of Aβ.…”

Section: Mrna Amplification Process May Preserve the Protein-encodingmentioning

confidence: 99%

Protein-Encoding RNA-to-RNA Information Transfer in Mammalian Cells: Principles of RNA-Dependent mRNA Amplification

Volloch¹

2019

Preprint

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The transfer of protein-encoding genetic information from DNA to RNA to protein, a process formalized as the "Central Dogma of Molecular Biology", has undergone a significant evolution since its inception. It was amended to account for the information flow from RNA to DNA, the reverse transcription, and for the information transfer from RNA to RNA, the RNA-dependent RNA synthesis. These processes, both potentially leading to protein production, were initially described only in viral systems, and although RNAdependent RNA polymerase activity was shown to be present, and RNA-dependent RNA synthesis found to occur in mammalian cells, its function was presumed to be restricted to regulatory. However, recent results, obtained in several systems, strongly indicate the occurrence of protein-encoding RNA to RNA information transfer in mammalian cells. It can result in the rapid production of the extraordinary quantities of specific proteins as was seen in cases of terminal cellular differentiation and during cellular deposition of extracellular matrix molecules. A malfunction of this process may be involved in pathologies associated either with the deficiency of a protein normally produced by this mechanism or with the abnormal abundance of a protein or of its C-terminal fragment. It seems to be responsible for some types of familial thalassemia and may underlie the overproduction of beta amyloid in sporadic Alzheimer's disease. The increased understanding of components and mechanisms involved in RNA-dependent mammalian mRNA amplification could open up new approaches not only for therapeutic interference in multiple pathologies but also for novel and powerful forms of bioengineering. The aim of the present article is to systematize the current knowledge and understanding of this pathway. The outlined framework introduces unexpected features of the mRNA amplification such as its second Tier, a physiologically occurring intracellular PCR, iPCR, a "Two-Tier Paradox" and RNA "Dark Matter". It also describes novel experimental bioengineering designs and may serve as a basis for new directions of investigations into the mechanisms underlying the mammalian mRNA amplification processes.

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“…The size of Aβ ranges from 36 to 43 amino acids, with Aβ40 being the most abundant species normally formed. Studies of the inherited forms of the disease, FAD, strongly indicated that cerebral Aβ accumulation is essential for and underlies the etiology of the disease (4)(5)(6). This notion was formalized in a putative theory of AD known as "Amyloid Cascade Hypothesis", ACH (7)(8)(9)(10)(11)(12).…”

mentioning

confidence: 99%

“…In terms of the ACH, there is little doubt that the abnormal processing of βAPP and increased production of total Aβ or its 42-amino acid isoform are pivotal events in the pathogenesis of FAD. Although the number of individuals affected by FAD is substantial, in relative terms this form of the disease is quite rare, representing less than 5% (less than 1% by some estimates) of the total Alzheimer's disease burden (5,13,14). Since the pathological lesions and symptoms in the non-hereditary form of the disease, SAD, are analogous to those seen in the familial forms, it has been assumed that abnormal amyloidogenic proteolytic processing of βAPP also underlies the pathogenesis of SAD (4,5).…”

mentioning

confidence: 99%

Results of BACE1-Inhibitor Clinical Trials Confirm Key Predictions For App-Independent Generation of Beta-Amyloid in Sporadic AD

Volloch¹,

Rits²

2018

Preprint

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The present article analyzes the results of recent clinical trials of beta secretase inhibition in sporadic Alzheimer' disease (SAD), considers the striking dichotomy between successes in tests of BACE1 inhibitors in healthy subjects and familial AD (FAD) models versus persistent failures of clinical trials and interprets it as a confirmation of key predictions for a mechanism of APP-independent, beta secretase inhibition-resistant production of beta amyloid in SAD, previously proposed by us. In the light of this concept, FAD and SAD should be regarded as distinctly different diseases as far as beta-amyloid generation mechanisms are concerned, and whereas beta secretase inhibition would be neither applicable nor effective in treatment of SAD, the BACE1 inhibitor(s) deemed failed in SAD trials could be perfectly suitable for treatment of FAD. Moreover, targeting the aspects of AD other than cleavages of the APP by beta and alpha secretases should have analogous impacts in both FAD and SAD.

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The Genetics of Alzheimer’s Disease

Cited by 85 publications

References 158 publications

MALDI‐imaging analyses of honeybee brains exposed to a neonicotinoid insecticide

MALDI‐imaging analyses of honeybee brains exposed to a neonicotinoid insecticide

Protein-Encoding RNA-to-RNA Information Transfer in Mammalian Cells: Principles of RNA-Dependent mRNA Amplification

Results of BACE1-Inhibitor Clinical Trials Confirm Key Predictions For App-Independent Generation of Beta-Amyloid in Sporadic AD

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