Alzheimer's Disease as a Membrane‐Associated Enzymopathy of β‐Amyloid Precursor Protein (APP) Secretases

Hata, Satoshi; Saito, Yuhki; Suzuki, Toshiharu

doi:10.1002/9783527634323.ch8

Cited by 2 publications

(4 citation statements)

References 62 publications

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“…These results could provide the hypothesis on a different route by which, together with the others above described, metformin could be negatively correlated to AD pathogenesis. Indeed, in the wide structural poly-morphism of Aβ oligomers, the accredited assumption is that, rather than mature fibrils, the species more involved in pathogenesis of AD are prefibrillar oligomeric species that form at the beginning of the process [ 51 , 52 ]. These species expose larger hydrophobic surfaces to the solvent and, therefore, could directly interact with cell membranes influencing calcium homeostasis and ROS production.…”

Section: Discussionmentioning

confidence: 99%

Biological and biophysics aspects of metformin-induced effects: cortex mitochondrial dysfunction and promotion of toxic amyloid pre-fibrillar aggregates

Picone

Vilasi

Librizzi

et al. 2016

Aging

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The onset of Alzheimer disease (AD) is influenced by several risk factors comprising diabetes. Within this context, antidiabetic drugs, including metformin, are investigated for their effect on AD. We report that in the C57B6/J mice, metformin is delivered to the brain where activates AMP-activated kinase (AMPK), its molecular target. This drug affects the levels of β-secretase (BACE1) and β-amyloid precursor protein (APP), promoting processing and aggregation of β-amyloid (Aβ), mainly in the cortex region. Moreover, metformin induces mitochondrial dysfunction and cell death by affecting the level and conformation of Translocase of the Outer Membrane 40 (TOM40), voltage-dependent anion-selective channels 1 (VDAC1) and hexokinase I (HKI), proteins involved in mitochondrial transport of molecules, including Aβ. By using biophysical techniques we found that metformin is able to directly interact with Aβ influencing its aggregation kinetics and features. These findings indicate that metformin induces different adverse effects, leading to an overall increase of the risk of AD onset.

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Section: Discussionmentioning

confidence: 99%

Biological and biophysics aspects of metformin-induced effects: cortex mitochondrial dysfunction and promotion of toxic amyloid pre-fibrillar aggregates

Picone

Vilasi

Librizzi

et al. 2016

Aging

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“…Alzheimer's precursor protein is cleaved in lipid rafts where secretases are most abundant and membrane perturbations that increased trafficking of APP to rafts can increase production of Aβ . The cleaved peptide may be retained by the membrane as soluble Aβ oligomers have high affinity for the head group charge of phospholipids, for GM1 ganglioside as well as other lipids and proteins . Pre‐fibrillar membrane‐associated Aβ can be visualized by immunogold electron microscopy in mutant mice (Figure ).…”

Section: Membrane Topology Of Misfolded Proteinsmentioning

confidence: 99%

“…The factors which promote Aβ aggregation on membranes are incompletely understood but increased concentrations of Aβ 1–42 due to changes in γ secretase activity and reduction in interstitial drainage may be contributory. It is well established that Aβ 1–42 forms fibrils more quickly in vitro than Aβ 1–40 .…”

Section: Membrane Topology Of Misfolded Proteinsmentioning

confidence: 99%

“…The binding of Aβ to membranes appears to catalyse oligomerization, and these oligomeric forms of Aβ have still greater affinity for phospholipids . Once insoluble Aβ 1–42 oligomers are released into the extracellular space, ApoE and extracellular matrix components such as the highly sulphated proteoglycans may facilitate assembly into amyloid fibrils.…”

Section: Membrane Topology Of Misfolded Proteinsmentioning

confidence: 99%

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Review: Membrane‐associated misfolded protein propagation in natural transmissible spongiform encephalopathies (TSEs), synthetic prion diseases and Alzheimer's disease

Jeffrey

2013

Neuropathology Appl Neurobio

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Protein misfolding has long been recognized as a primary cause of systemic amyloidosis and, increasingly, template-mediated misfolding of native host proteins is now also considered to be central pathogenetic events in some neurodegenerative diseases. Alzheimer's disease, naturally occurring transmissible spongiform encephalopathies (TSEs) and experimental disorders caused by misfolded prion protein (PrP) generated in vitro all share an imbalance of protein synthesis, aggregation and clearance that leads to protein aggregation, prompting some to suggest that Alzheimer's disease is caused by a prion-like mechanism. In TSEs, the host-coded, glycosyl-phosphoinositol (GPI) membrane-anchored prion protein (PrP(c) ) is misfolded into disease-associated, putatively infectious aggregates known as prions. In Alzheimer's disease the membrane-spanning Alzheimer's precursor protein (APP) is progressively cleaved within the plasmalemma to form Aβ peptide fragments that can form pathogenic extracellular aggregates while microtubule-associated tau proteins may also aggregate within neurones. Oligomeric Aβ peptides and full-length misfolded PrP show a common potential to convert native protein and aggregate on plasma membranes before subsequent release to form amyloid fibrils in the extracellular space. However, the nature, membrane topography and processing of the precursor and propagated proteins in prion and Alzheimer's disease all differ, and each group of diseases has distinctive spectra of additional pathological changes and clinical signs suggesting that fundamentally different disease mechanisms are involved.

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Alzheimer's Disease as a Membrane‐Associated Enzymopathy of β‐Amyloid Precursor Protein (APP) Secretases

Cited by 2 publications

References 62 publications

Biological and biophysics aspects of metformin-induced effects: cortex mitochondrial dysfunction and promotion of toxic amyloid pre-fibrillar aggregates

Biological and biophysics aspects of metformin-induced effects: cortex mitochondrial dysfunction and promotion of toxic amyloid pre-fibrillar aggregates

Review: Membrane‐associated misfolded protein propagation in natural transmissible spongiform encephalopathies (TSEs), synthetic prion diseases and Alzheimer's disease

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