Amylin Enhances Amyloid-β Peptide Brain to Blood Efflux Across the Blood-Brain Barrier

Mohamed, Loqman A.; Zhu, Haihao; Mousa, Youssef M.; Wang, Erming; Qiu, Wei Qiao; Kaddoumi, Amal

doi:10.3233/jad-160800

Cited by 21 publications

(13 citation statements)

References 57 publications

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“…This effect was inhibited by amylin receptor antagonists and RAMP3 knockdown, further suggesting a role of AmR in mediating Aβ transport out of the brain across the BBB (Mohamed et al, 2017). Additionally, amylin treatments enhanced the Aβ brain-to-blood clearance likely by relocating low density lipoprotein receptor-related protein 1 (LRP1) from the cytosol to the membrane at the BBB.…”

Section: Elucidating the Mechanism Of Amylin Effects On Learning And mentioning

confidence: 99%

Amylin and its G-protein-coupled receptor: A probable pathological process and drug target for Alzheimer’s disease

Qiu

2017

Neuroscience

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G-protein-coupled receptors (GPCRs) are shown to be involved in Alzheimer’s disease (AD) pathogenesis. However, because GPCRs include a large family of membrane receptors, it is unclear which specific GPCR or pathway with rational ligands can become effective therapeutic targets for AD. Amylin receptor (AmR) is a GPCR that mediates several activities, such as improving glucose metabolism, relaxing cerebrovascular structure, modulating inflammatory reactions and potentially enhancing neural regeneration. Recent studies show that peripheral treatments with amylin or its clinical analog, pramlintide, reduced several components of AD pathology, including amyloid plaques, tauopathy, neuroinflammation and other components in the brain, corresponding with improved learning and memory in AD mouse models. Because amylin shares a similar secondary structure with amyloid-β peptide (Aβ), I propose that the AmR/GPCR pathway is disturbed by a large amount of Aβ in the AD brain, leading to tau phosphorylation, neuroinflammation and neuronal death in the pathological cascade. Amylin-type peptides, readily crossing the blood brain barrier (BBB), are the rational ligands to enhance this GPCR pathway and may exhibit utility as novel therapeutic agents for treating AD.

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Section: Elucidating the Mechanism Of Amylin Effects On Learning And mentioning

confidence: 99%

Amylin and its G-protein-coupled receptor: A probable pathological process and drug target for Alzheimer’s disease

Qiu

2017

Neuroscience

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“…Amylin and Aβ have several common features such as having similar β-sheet structures 25 , binding to the same amylin receptor 26 , and being degraded by insulin degrading enzyme (IDE) 27 .Several studies have shown that amylin is involved in the pathogenesis of AD by inducing neuroinflammation and apoptosis 28 , but little is known about the mechanism by which amylin exacerbates AD pathology. On the other hand, multiple studies have shown that amylin ameliorated AD pathology by decreasing neuroinflammation and increasing Aβ clearance from brain to blood [29][30][31][32] . In this study, we investigated the effect of amylin and its alanog, pramlintide, on Aβ pathology, and identified a novel aspect of amylin and pramlintide in increasing the amyloidogenic processing of APP in TgSwDI mouse, a model for cerebral amyloid angiopathy (CAA) and AD, where both peptides increased γ-secretase complex level and APP localization in lipid rafts.…”

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confidence: 99%

Amylin and pramlintide modulate γ-secretase level and APP processing in lipid rafts

Mousa

Abdallah

Hwang

et al. 2020

Sci Rep

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A major characteristic of Alzheimer's disease (AD) is the accumulation of misfolded amyloid-β (Aβ) peptide. Several studies linked AD with type 2 diabetes due to similarities between Aβ and human amylin. This study investigates the effect of amylin and pramlintide on Aβ pathogenesis and the predisposing molecular mechanism(s) behind the observed effects in TgSwDI mouse, a cerebral amyloid angiopathy (CAA) and AD model. Our findings showed that thirty days of intraperitoneal injection with amylin or pramlintide increased Aβ burden in mice brains. Mechanistic studies revealed both peptides altered the amyloidogenic pathway and increased Aβ production by modulating amyloid precursor protein (App) and γ-secretase levels in lipid rafts. in addition, both peptides increased levels of B4GALNT1 enzyme and GM1 ganglioside, and only pramlintide increased the level of GM2 ganglioside. Increased levels of GM1 and GM2 gangliosides play an important role in regulating amyloidogenic pathway proteins in lipid rafts. increased brain Aβ burden by amylin and pramlintide was associated with synaptic loss, apoptosis, and microglia activation. In conclusion, our findings showed amylin or pramlintide increase Aβ levels and related pathology in tgSwDi mice brains, and suggest that increased amylin levels or the therapeutic use of pramlintide could increase the risk of AD.Alzheimer's disease (AD) is a complex neurodegenerative disorder characterized by multiple dysregulated neurobiological networks and cellular functions, neuronal death, and memory loss 1 . The major hallmarks for AD include amyloid-β (Aβ) deposits and neurofibrillary tangles of hyper-phosphorylated tau protein 1,2 . Aβ is produced from the amyloid-β precursor protein (APP), which, after synthesis, traffics to the Golgi apparatus and eventually to plasma membrane 3 . The majority of plasma membrane bound APP is rapidly endocytosed 3 , while approximately 10% of the total APP is processed in the plasma membrane by α-secretase to release soluble APP-α (sAPP-α) 4 . Alternatively, APP can be processed by β-site APP cleaving enzyme 1 (BACE1) in plasma membrane, trans-Golgi, and early endosomes to produce soluble APP-β (sAPP-β) and β-C-terminal fragments (β-CTF), followed by subsequent proteolytic cleavage of β-CTF by γ-secretase to release Aβ 4 . Besides Aβ production, another contributing factor to Aβ accumulation in AD is the failure to clear Aβ from the brain 5 , and across the blood-brain barrier (BBB) 6 .The accumulation of Aβ due to decreased clearance or increased production leads to multiple dysregulated cellular functions including synaptic loss and neuroinflammation 7,8 . Aβ initiates synaptic loss by down-regulating synaptic markers in AD including the pre-synaptic marker SNAP-25 and synapsin I and post-synaptic marker PSD-95 9 . Moreover, the accumulation of Aβ in the brain parenchyma of AD patients is associated with strong inflammatory processes and glial cells activation 7 .Mounting evidence supports the localization of APP, BACE1 and each of the four core subu...

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“…High-speed AFM (HS-AFM) enabled the kinetic measurement of the structural dynamics of biological molecular processes [79][80][81][82][83][84] including amyloid aggregation [93,[108][109][110][111][112][113][114][115][116]. Here, we show that HS-AFM links structural and dynamics studies, reviewing recent HS-AFM studies and including our findings for Aβ42 [93] and amylin [116], which is associated with not only type II diabetes but also AD [117][118][119][120][121][122][123].…”

Section: Introductionmentioning

confidence: 64%

“…Amylin crosses the blood-brain barrier (BBB) [157][158][159], and its aggregate deposition is found in the brains of type II diabetes patients with AD [121]. The mechanisms underlying the pathological [122,123] and suppressive [117][118][119][120] effects of amylin to AD remain controversial [160].…”

Section: Aggregation Inhibition By Synthetic Polymersmentioning

confidence: 99%

High-Speed Atomic Force Microscopy Reveals the Structural Dynamics of the Amyloid-β and Amylin Aggregation Pathways

Watanabe‐Nakayama

Sahoo

Ramamoorthy

et al. 2020

IJMS

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Individual Alzheimer’s disease (AD) patients have been shown to have structurally distinct amyloid-β (Aβ) aggregates, including fibrils, in their brain. These findings suggest the possibility of a relationship between AD progression and Aβ fibril structures. Thus, the characterization of the structural dynamics of Aβ could aid the development of novel therapeutic strategies and diagnosis. Protein structure and dynamics have typically been studied separately. Most of the commonly used biophysical approaches are limited in providing substantial details regarding the combination of both structure and dynamics. On the other hand, high-speed atomic force microscopy (HS-AFM), which simultaneously visualizes an individual protein structure and its dynamics in liquid in real time, can uniquely link the structure and the kinetic details, and it can also unveil novel insights. Although amyloidogenic proteins generate heterogeneously aggregated species, including transient unstable states during the aggregation process, HS-AFM elucidated the structural dynamics of individual aggregates in real time in liquid without purification and isolation. Here, we review and discuss the HS-AFM imaging of amyloid aggregation and strategies to optimize the experiments showing findings from Aβ and amylin, which is associated with type II diabetes, shares some common biological features with Aβ, and is reported to be involved in AD.

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Amylin Enhances Amyloid-β Peptide Brain to Blood Efflux Across the Blood-Brain Barrier

Cited by 21 publications

References 57 publications

Amylin and its G-protein-coupled receptor: A probable pathological process and drug target for Alzheimer’s disease

Amylin and its G-protein-coupled receptor: A probable pathological process and drug target for Alzheimer’s disease

Amylin and pramlintide modulate γ-secretase level and APP processing in lipid rafts

High-Speed Atomic Force Microscopy Reveals the Structural Dynamics of the Amyloid-β and Amylin Aggregation Pathways

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