Central Nervous System and Other Effects

Young, Andrew

doi:10.1016/s1054-3589(05)52017-9

Cited by 7 publications

(7 citation statements)

References 18 publications

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“…While the concentration used to cause neurotoxicity in rat cortical neurons after two to four days’ exposure is 50 μM (May et al, 1993), the average fasting plasma amylin concentrations are in the range of 4–25 pmol/l in healthy humans (Nyholm et al, 1998), and the peak of amylin in the amylin treatment we conducted for the mice was ~1 nmol/l. In addition, the half-life of exogenous amylin or pramlintide is about 20–45 min in vivo (Colburn et al, 1996; Young, 2005) (our own data not shown). A recent paper demonstrates that low vs. high concentrations of amylin bind different receptors (Zhang et al, 2017).…”

Section: Discussionmentioning

confidence: 77%

Amylin receptor ligands reduce the pathological cascade of Alzheimer's disease

et al. 2017

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Amylin is an important gut-brain axis hormone. Since amylin and amyloid-β peptide (Aβ) share similar β sheet secondary structure despite not having the same primary sequences, we hypothesized that the accumulation of Aβ in the brains of subjects with Alzheimer's disease (AD) might compete with amylin for binding to the amylin receptor (AmR). If true, adding exogenous amylin type peptides would compete with Aβ and reduce the AD pathological cascade, improving cognition. Here we report that a 10-week course of peripheral treatment with human amylin significantly reduced multiple different markers associated with AD pathology, including reducing levels of phospho-tau, insoluble tau, two inflammatory markers (Iba1 and CD68), as well as cerebral Aβ. Amylin treatment also led to improvements in learning and memory in two AD mouse models. Mechanistic studies showed that an amylin receptor antagonist successfully antagonized some protective effects of amylin in vivo, suggesting that the protective effects of amylin require interaction with its cognate receptor. Comparison of signaling cascades emanating from AmR suggest that amylin electively suppresses activation of the CDK5 pathway by Aβ. Treatment with amylin significantly reduced CDK5 signaling in a receptor dependent manner, dramatically decreasing the levels of p25, the active form of CDK5 with a corresponding reduction in tau phosphorylation. This is the first report documenting the ability of amylin treatment to reduce tauopathy and inflammation in animal models of AD. The data suggest that the clinical analog of amylin, pramlintide, might exhibit utility as a therapeutic agent for AD and other neurodegenerative diseases.

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Section: Discussionmentioning

confidence: 77%

Amylin receptor ligands reduce the pathological cascade of Alzheimer's disease

et al. 2017

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“…Amylin receptor (AmR) is one type of GPCR and is composed of the calcitonin receptor (CTR) complexed with different receptor-activity-modifying proteins (RAMPs) (Gebre-Medhin et al, 1998; Hay et al, 2015). CTR and RAMPs are expressed in the brain, including the regions related to AD like locus coeruleus, cortex and hippocampus (Nakamoto et al, 2000; Young, 2005a). Individual RAMPs have been disrupted, revealing a range of phenotypes in the mouse models.…”

Section: Is Amylin-mediated G-protein-coupled Receptor/pathway Disturmentioning

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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“…While the average fasting plasma amylin concentrations are in the range of 4–25 pM in healthy humans [46], amylin aggregates only when the concentration reaches to the μM level [13, 47]. The peak of the amylin concentration in the amylin treatment we conducted for AD mouse models was ~1–4 nM, and the half-life of exogenous amylin or pramlintide is approximately 20–45 min in vivo [48, 49] (our own data not shown). Given that pramlintide does not aggregate, even the peak concentration of the amylin treatment in vivo was far from the concentration leading to amylin aggregation.…”

Section: Discussionmentioning

confidence: 99%

Effects of Amylin Against Amyloid-β-Induced Tauopathy and Synapse Loss in Primary Neurons

Gan

Yao

et al. 2019

JAD

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Recent studies demonstrate that peripheral amylin treatment reduces pathology in mouse models of Alzheimer’s disease (AD). However, soluble and aggregated amylin are distinct species; while amylin is a physiological neuropeptide, amylin aggregation is a pathological factor for diabetes. We thus hypothesized that because of their similarity in secondary structures, amylin antagonizes amyloid-β peptide (Aβ) induced AD pathology in neurons with a dose dependent pattern. To test the hypothesis, we conducted both in vitro and in vivo experiments with different doses of amylin and with its analog, pramlintide. Here we report that a high concentration of either Aβ or amylin alone induced tau phosphorylation (pTau) in primary neurons. Interestingly, with a low concentration, amylin had direct effects to reverse the Aβ induced pTau, as well as damaged neuronal synapses and neurite disorganization. However, when the concentration was high (10.24 μM), amylin lost the effects against the Aβ induced cellular AD pathology and, together with Aβ, worsened tauopathy in neurons. In the 5XFAD AD mouse model, daily peripheral amylin treatment with a low dose (200 μg/kg) more effectively reduced amyloid burden, and increased synapse, but with a high dose (800 μg/kg) it more effectively reduced tauopathy. Correspondingly, amylin treatment improved learning and memory in these mice. It demonstrates that amylin has a dose-dependent U-shape effect against AD pathogenesis. Within a physiological range, amylin is a neuroprotective hormone against AD in neurons; but when both Aβ and amylin concentrations are elevated, imbalance of Aβ and amylin may contribute to brain AD pathogenesis.

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Central Nervous System and Other Effects

Cited by 7 publications

References 18 publications

Amylin receptor ligands reduce the pathological cascade of Alzheimer's disease

Amylin receptor ligands reduce the pathological cascade of Alzheimer's disease

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

Effects of Amylin Against Amyloid-β-Induced Tauopathy and Synapse Loss in Primary Neurons

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