Role of the cell membrane interface in modulating production and uptake of Alzheimer's beta amyloid protein

Bharadwaj, Prashant; Solomon, Tanya; Malajczuk, Chris J.; Mancera, Ricardo L.; Howard, Mark J.; Arrigan, Damien W. M.; Newsholme, P.; Martins, Ralph N.

doi:10.1016/j.bbamem.2018.03.015

Cited by 53 publications

(54 citation statements)

References 183 publications

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“…www.nature.com/scientificreports www.nature.com/scientificreports/ of hIAPP in promoting the uptake of Aβ42 in neuronal cells (SHSY-5Y), indicating that Aβ42-hIAPP heterocomplexes have an enhanced ability to interact and permeabilize cell membranes 37 . A recent report also demonstrated that hIAPP-Aβ heterocomplexes adsorb, aggregate, and permeabilize the isolated β-cell membrane significantly slower than pure hIAPP, however, at a rate that is much faster than that of pure Aβ 38 .…”

Section: Discussionmentioning

confidence: 99%

Amylin and beta amyloid proteins interact to form amorphous heterocomplexes with enhanced toxicity in neuronal cells

Bharadwaj

Solomon

Sahoo

et al. 2020

Sci Rep

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Human pancreatic islet amyloid polypeptide (hiApp) and beta amyloid (Aβ) can accumulate in Type 2 diabetes (T2D) and Alzheimer's disease (AD) brains and evidence suggests that interaction between the two amyloidogenic proteins can lead to the formation of heterocomplex aggregates. However, the structure and consequences of the formation of these complexes remains to be determined. The main objective of this study was to characterise the different types and morphology of Aβ-hiApp heterocomplexes and determine if formation of such complexes exacerbate neurotoxicity. We demonstrate that hiApp promotes Aβ oligomerization and formation of small oligomer and large aggregate heterocomplexes. Co-oligomerized Aβ42-hIAPP mixtures displayed distinct amorphous structures and a 3-fold increase in neuronal cell death as compared to Aβ and hIAPP alone. However, in contrast to hIAPP, non-amyloidogenic rat amylin (rIAPP) reduced oligomer Aβ-mediated neuronal cell death. rIAPP exhibited reductions in Aβ induced neuronal cell death that was independent of its ability to interact with Aβ and form heterocomplexes; suggesting mediation by other pathways. Our findings reveal distinct effects of IAPP peptides in modulating Aβ aggregation and toxicity and provide new insight into the potential pathogenic effects of Aβ-IAPP hetero-oligomerization and development of IAPP based therapies for AD and T2D. Epidemiological and clinical evidence suggests a strong association between Type 2 diabetes (T2D) and Alzheimer's disease (AD), with T2D patients having a significantly higher risk of developing AD compared to non-diabetic individuals 1-3. Both AD and T2D share common pathogenic markers including inflammation, oxidative stress, metabolic dysfunction and accumulation of the amyloidogenic proteins including beta amyloid (Aβ) and pancreatic islet amyloid polypeptide (IAPP or amylin) 4,5. Aβ is the main component of senile plaques in the AD brain 6. Similar to Aβ, human IAPP (hIAPP) containing deposits are observed in the T2D pancreas 7. The accumulation of aggregated Aβ or hIAPP in the brain and pancreas has been shown to be associated with cell dysfunction and death 8,9. Aβ is produced via the N-terminal proteolytic cleavage of amyloid precursor protein (APP) by BACE1 and at the C-terminus by γ-secretase, with the final Aβ length varying from 39 to 43 amino acids 10. Aβ42 is the central component of senile plaques observed in the AD brain and is considered the main neurotoxic form 11,12. hIAPP is cleaved from the pre-pro form of IAPP and subsequently converted into a 37-amino acid structure by pancreatic β-cell secretory granules 7. Mature hIAPP modulates insulin-sensitive glucose uptake and

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Section: Discussionmentioning

confidence: 99%

Amylin and beta amyloid proteins interact to form amorphous heterocomplexes with enhanced toxicity in neuronal cells

Bharadwaj

Solomon

Sahoo

et al. 2020

Sci Rep

Self Cite

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“…For instance, Ab may compete with insulin and bind to its receptors at the periphery, impairing pancreatic b-cells and leading to insulin resistance and glucose dysmetabolism [132,133]. This may in turn exacerbate Ab deposition [134,135], creating a vicious cycle of dysfunctional CNS insulin signalling, oxidative stress and neuroinflammation, culminating in cognitive deficits [136]. Despite controversial, this may also involve the hyperphosphorylated Tau-induced destabilization of microtubules in bcells, blunting insulin secretion [137] and insulinmediated trafficking of glucose transporter-4 (GLUT4)-containing vesicles to the plasma membrane.…”

Section: Restoring Insulin Action and Glucose Metabolism In Ad: Our Shomentioning

confidence: 99%

Current and emerging avenues for Alzheimer's disease drug targets

et al. 2019

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Loera-Valencia R, Cedazo-Minguez A, ). Current and emerging avenues for Alzheimer's disease drug targets (Review). J Intern Med 2019; 286: 398-437.Alzheimer's disease (AD), the most frequent cause of dementia, is escalating as a global epidemic, and so far, there is neither cure nor treatment to alter its progression. The most important feature of the disease is neuronal death and loss of cognitive functions, caused probably from several pathological processes in the brain. The main neuropathological features of AD are widely described as amyloid beta (Ab) plaques and neurofibrillary tangles of the aggregated protein tau, which contribute to the disease. Nevertheless, AD brains suffer from a variety of alterations in function, such as energy metabolism, inflammation and synaptic activity. The latest decades have seen an explosion of genes and molecules that can be employed as targets aiming to improve brain physiology, which can result in preventive strategies for AD. Moreover, therapeutics using these targets can help AD brains to sustain function during the development of AD pathology. Here, we review broadly recent information for potential targets that can modify AD through diverse pharmacological and nonpharmacological approaches including gene therapy. We propose that AD could be tackled not only using combination therapies including Ab and tau, but also considering insulin and cholesterol metabolism, vascular function, synaptic plasticity, epigenetics, neurovascular junction and blood-brain barrier targets that have been studied recently. We also make a case for the role of gut microbiota in AD. Our hope is to promote the continuing research of diverse targets affecting AD and promote diverse targeting as a near-future strategy. ReviewInsoluble Ab fibrils are taken into consideration as the main responsible for spine pathology. On the other hand, in both transgenic mouse models of AD and human AD brain, synapse defects and memory loss correlate weakly with the presence of Ab Current and novel Alzheimer´s disease therapy targets / R. Loera-Valencia et al.

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“…Loss of PM integrity is also a pathomechanism of AD and PD, and most likely other proteinopathies. Membrane lipids play an important role in the kinetics of Aβ and αsyn aggregation and, in turn, resultant toxicity [125][126][127] . Lipids influence the aggregation process through lipidinduced conformational changes 122,126,128,129 or mass action 130,131 (i.e.…”

Section: Pathological Conditions: Neurodegenerative Diseasesmentioning

confidence: 99%

“…Well-ordered, oligomeric membrane-spanning pores are formed in a defined manner. Firstly, monomeric α-syn accumulates at the membrane by mass action 130 or oligomeric α-syn 122 or Aβ 126,128 species translocate to the membrane and orient their hydrophobic residues towards the hydrophobic core of the lipid bilayer. Once embedded, a ring-like structure with a central hole is formed.…”

Section: Pathological Conditions: Neurodegenerative Diseasesmentioning

confidence: 99%

Plasma membrane integrity in health and disease: significance and therapeutic potential

2021

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Maintenance of plasma membrane integrity is essential for normal cell viability and function. Thus, robust membrane repair mechanisms have evolved to counteract the eminent threat of a torn plasma membrane. Different repair mechanisms and the bio-physical parameters required for efficient repair are now emerging from different research groups. However, less is known about when these mechanisms come into play. This review focuses on the existence of membrane disruptions and repair mechanisms in both physiological and pathological conditions, and across multiple cell types, albeit to different degrees. Fundamentally, irrespective of the source of membrane disruption, aberrant calcium influx is the common stimulus that activates the membrane repair response. Inadequate repair responses can tip the balance between physiology and pathology, highlighting the significance of plasma membrane integrity. For example, an over-activated repair response can promote cancer invasion, while the inability to efficiently repair membrane can drive neurodegeneration and muscular dystrophies. The interdisciplinary view explored here emphasises the widespread potential of targeting plasma membrane repair mechanisms for therapeutic purposes.

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Role of the cell membrane interface in modulating production and uptake of Alzheimer's beta amyloid protein

Cited by 53 publications

References 183 publications

Amylin and beta amyloid proteins interact to form amorphous heterocomplexes with enhanced toxicity in neuronal cells

Amylin and beta amyloid proteins interact to form amorphous heterocomplexes with enhanced toxicity in neuronal cells

Current and emerging avenues for Alzheimer's disease drug targets

Plasma membrane integrity in health and disease: significance and therapeutic potential

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