Author: Jhamandas, Jack ; Fu, Wen ; Kaur, Kamaljit ; MacTavish, David ; Vukojevic, Vlatka ; Westaway, David ; Patel, Aarti ; Goncharuk, Valeri ; Soudy, Rania

BACKGROUNDNeuroinflammation in the brain consequent to activation of microglia is viewed as an important component of Alzheimer's disease (AD) pathology. Amyloid beta (Aβ) protein is known to activate microglia and unleash an inflammatory cascade that eventually results in neuronal dysfunction and death. In this study, we sought to identify the presence of amylin receptors on human fetal and murine microglia and determine whether Aβ activation of the inflammasome complex and subsequent release of cytokines is mediated through these receptors.METHODSThe presence of dimeric components of the amylin receptor (calcitonin receptor and receptor activity modifying protein 3) were first immunohistochemically identified on microglia. Purified human fetal microglial (HFM) cultures were incubated with an in vivo microglial marker, DyLight 594-conjugated tomato lectin, and loaded with the membrane-permeant green fluorescent dye, Fluo-8L-AM for measurements of intracellular calcium [Ca²⁺]i. HFM and BV-2 cells were primed with lipopolysaccharide and then exposed to either human amylin or soluble oligomeric Aβ_1-42 prior to treatment with and without the amylin receptor antagonist, AC253. Changes in the inflammasome complex, NLRP3 and caspase-1, were examined in treated cell cultures with Western blot and fluorometric assays. RT-PCR measurements were performed to assess cytokine release. Finally, in vivo studies were performed in transgenic mouse model of AD (5xFAD) to examine the effects of systemic administration of AC253 on markers of neuroinflammation in the brain.RESULTSAcute applications of human amylin or Aβ_1-42 resulted in an increase in [Ca²⁺]i that could be blocked by the amylin receptor antagonist, AC253. Activation of the NLRP3 and caspase-1 and subsequent release of cytokines, TNFα and IL-1β, was diminished by AC253 pretreatment of HFMs and BV2 cells. In vivo, intraperitoneal administration of AC253 resulted in a reduction in microglial markers (Iba-1 and CD68), caspase-1, TNFα, and IL-1β. These reductions in inflammatory markers were accompanied by reduction in amyloid plaque and size in the brains of 5xFAD mice compared to controls.CONCLUSIONMicroglial amylin receptors mediate Aβ-evoked inflammation, and amylin receptor antagonists therefore offer an attractive therapeutic target for intervention in AD.

03 Feb 2017·Journal of Alzheimer's DiseaseQ3 · MEDICINE

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

Q3 · MEDICINE

Article

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

Findings from Alzheimer's disease (AD) mouse models showed that amylin treatment improved AD pathology and enhanced amyloid-β (Aβ) brain to blood clearance; however, the mechanism was not investigated. Using the Tg2576 AD mouse model, a single intraperitoneal injection of amylin significantly increased Aβ serum levels, and the effect was abolished by AC253, an amylin receptor antagonist, suggesting that amylin effect could be mediated by its receptor. Subsequent mechanistic studies showed amylin enhanced Aβ transport across a cell-based model of the blood-brain barrier (BBB), an effect that was abolished when the amylin receptor was inhibited by two amylin antagonists and by siRNA knockdown of amylin receptor Ramp3. To explain this finding, amylin effect on Aβ transport proteins expressed at the BBB was evaluated. Findings indicated that cells treated with amylin induced LRP1 expression, a major receptor involved in brain Aβ efflux, in plasma membrane fraction, suggesting intracellular translocation of LRP1 from the cytoplasmic pool. Increased LRP1 in membrane fraction could explain, at least in part, the enhanced uptake and transport of Aβ across the BBB. Collectively, our findings indicated that amylin induced Aβ brain to blood clearance through amylin receptor by inducing LRP1 subcellular translocation to the plasma membrane of the BBB endothelium.

01 Jan 2017·Alzheimer's & Dementia: Translational Research & Clinical Interventions

Cyclic AC253, a novel amylin receptor antagonist, improves cognitive deficits in a mouse model of Alzheimer's disease

Article

Author: Jhamandas, Jack ; Fu, Wen ; MacTavish, David ; Zajac, Jeffrey ; Kaur, Kamaljit ; Davey, Rachel ; Soudy, Rania ; Patel, Aarti ; Westaway, David

AbstractIntroductionAmylin receptor serves as a portal for the expression of deleterious effects of amyloid β‐protein (Aβ), a key pathologic hallmark of Alzheimer's disease. Previously, we showed that AC253, an amylin receptor antagonist, is neuroprotective against Aβ toxicity in vitro and abrogates Aβ‐induced impairment of hippocampal long‐term potentiation.MethodsAmyloid precursor protein–overexpressing TgCRND8 mice received intracerebroventricularly AC253 for 5 months. New cyclized peptide cAC253 was synthesized and administered intraperitoneally three times a week for 10 weeks in the same mouse model. Cognitive functions were monitored, and pathologic changes were quantified biochemically and immunohistochemically.ResultsAC253, when administered intracerebroventricularly, improves spatial memory and learning, increases synaptic integrity, reduces microglial activation without discernible adverse effects in TgCRND8 mice. cAC253 demonstrates superior brain permeability, better proteolytic stability, and enhanced binding affinity to brain amylin receptors after a single intraperitoneal injection. Furthermore, cAC253 administered intraperitoneally also demonstrates improvement in spatial memory in TgCRND8 mice.DiscussionAmylin receptor is a therapeutic target for Alzheimer's disease and represents a disease‐modifying therapy for this condition.

100 Deals associated with ACO-253

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Indication	Highest Phase	Country/Location	Organization	Date
Diabetes Mellitus, Type 2	Phase 1	-	Bristol Myers Squibb Co.	-
Diabetes Mellitus, Type 2	Phase 1	-	AstraZeneca Pharmaceuticals Co. Ltd.	-
Diabetes Mellitus, Type 2	Phase 1	US	Amylin Pharmaceuticals, Inc.	-
Obesity	Phase 1	US	Amylin Pharmaceuticals, Inc.	-
Obesity	Phase 1	-	AstraZeneca Pharmaceuticals Co. Ltd.	-
Obesity	Phase 1	-	Bristol Myers Squibb Co.	-

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