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CAC-253 is the cyclised form of AC253, a 24-residue peptide that BLOCKS the amylin receptor rather than activating it, which makes it the mirror image of the amylin drugs being developed for obesity. It is a preclinical Alzheimer's tool from a single academic laboratory, built on the finding that amyloid beta acts through the amylin receptor [2]. Cyclisation raised its serum half-life from one hour to seven [1]. No human has ever taken it.
- Improved memory and reduced amyloid plaque in transgenic mice
- Cyclisation raised serum half-life from one hour to seven and improved potency
- Intact peptide confirmed in brain by mass spectrometry, which most peptide claims cannot show
- No sedation, motor signs or weight loss in mice; no human exposure of any kind
Mechanism
The starting point is an unusual claim that has held up: amyloid beta and human amylin both act on the amylin 3 receptor, a calcitonin receptor paired with a modifying protein, and blocking that receptor blocks their effects. AC253 stops the calcium influx, kinase signalling and cell death that amyloid beta triggers in cultured cells [2], restores the that amyloid beta and amylin suppress in hippocampal slices [3], prevents amyloid-driven inflammasome activation in [4], and blocks amyloid's effects on human fetal neurons [5].
CAC-253 is the same 24-residue sequence with a cysteine added at each end and a disulfide bond joining them. That ring improves everything measurable: potency at the receptor rises from about 0.85 to 0.3 micromolar, binding affinity from 2.6 to 1.45 micromolar, serum from one hour to seven, and brain half-life reaches about sixteen hours [1]. Uptake into cells is energy-dependent and partly clathrin-mediated, and brain uptake rises in mice whose amylin receptors are upregulated and falls in mice with fewer of them, which is the kind of target-dependence that argues the mechanism is real [1].
⚠️ Two numbers work against it, and neither is discussed in the Alzheimer's papers. Brain exposure after injection reaches 10 to 100 nanomolar, about a tenth of a percent of the injected dose, against a receptor IC50 of roughly 300 nanomolar; the concentration arriving is therefore below the potency measured for it [1]. And the parent inhibits adrenomedullin binding with an IC50 of 25 nanomolar [7], making it roughly a hundredfold more potent at that receptor than at the amylin receptor it is named for.
receptor fingerprint
Adrenomedullin receptorInhibitor
Amylin 3 receptor (AMY3)Antagonist
Amyloid plaque burdenReducer
Evidencehow good the literature is
The preclinical evidence is unusually careful and entirely preclinical.
The main study gave transgenic mice 200 micrograms per kilogram three times weekly for ten weeks from three and a half months of age, blinded, with ten animals per group. Treated mice found the hidden platform faster and remembered its location better a day later, and had significantly fewer and smaller amyloid plaques [1]. A comparator arm delivering the uncyclised parent directly into the brain for five months improved two memory tasks and raised synaptic proteins by 30 to 40 percent while halving a microglial activation marker, though its plaque reduction was only a non-significant trend [1].
The brain-exposure work deserves credit: intact peptide was confirmed in brain tissue by liquid chromatography and tandem mass spectrometry, not merely inferred from a label [1]. That is the standard most peptide brain-penetration claims fail.
⚠️ Three limits. Wild-type mice given the compound showed no change on any measure, so there is no evidence of enhancement in a normal brain. Brain concentration sits below the compound's own receptor potency. And no clinical trial of any amylin receptor antagonist has ever been registered.
Dosingtypical ranges, not medical advice
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Safetyrisks and cautions, not medical advice
There is no human safety data of any kind. No trial of AC253 or its cyclic form has ever been registered, no human has been exposed, and no toxicology package has been published.
What exists is the absence of gross toxicity in small groups of mice: roughly forty animals over ten weeks of intraperitoneal injection showed no sedation, motor signs, weight loss or hair loss, and mortality in a longer infusion study matched the untreated transgenic group [1].
⚠️ The pharmacology suggests where trouble would be looked for. The peptide family overlaps the calcitonin, amylin, calcitonin-gene-related-peptide and adrenomedullin receptors, and the parent is potent at the adrenomedullin site at 25 nanomolar [7]. Adrenomedullin signalling matters for blood pressure and vascular function, and calcitonin-family signalling matters for bone. Neither cardiovascular nor bone endpoints have been studied for this compound.
History
The idea behind this compound came from an observation in the late 2000s at the University of Alberta: amyloid beta and human amylin, two unrelated aggregating peptides, produced the same effects on neurons, and a known amylin receptor antagonist blocked both. That suggested the amylin receptor was a shared route through which amyloid does its damage, and made an antagonist a plausible Alzheimer's strategy at a time when the field was dominated by attempts to clear amyloid itself. AC253, a chimeric antagonist derived from the salmon calcitonin and amylin sequences, was the available tool but had a serum half-life of about an hour. Cyclising it through added cysteines fixed the stability problem and improved potency at the same time. The programme has since moved toward shorter peptides built on the same core sequence, and has not reached a clinical trial.
Resources
This entry is here for reference.
Research
- 1999first citedRat-2 fibroblasts express specific adrenomedullin receptors, but not calcitonin-gene-related-pe…
- 2019most recentShort amylin receptor antagonist peptides improve memory deficits in Alzheimer's disease mouse…
- 1.Cyclic AC253, a novel amylin receptor antagonist, improves cognitive deficits in a mouse model of Alzheimer's disease
- 2.Amyloid β (Aβ) peptide directly activates amylin-3 receptor subtype by triggering multiple intracellular signaling pathways.
- 3.Beta amyloid-induced depression of hippocampal long-term potentiation is mediated through the amylin receptor.
- 4.Role of microglial amylin receptors in mediating beta amyloid (Aβ)-induced inflammation.
- 5.Actions of β-amyloid protein on human neurons are expressed through the amylin receptor.
- 6.Short amylin receptor antagonist peptides improve memory deficits in Alzheimer's disease mouse model.
- 7.Rat-2 fibroblasts express specific adrenomedullin receptors, but not calcitonin-gene-related-peptide receptors, which mediate increased intracellular cAMP and inhibit mitogen-activated protein kinase activity.
7 listed here; entry last updated August 2026
Reviews
My notesprivate to this device
Limitations of the evidence
- Brain concentration reaches 10 to 100 nanomolar against its own receptor potency of about 300 nanomolar
- The parent peptide is roughly a hundredfold more potent at an adrenomedullin receptor than at the amylin receptor
- Wild-type mice showed no change on any measure, so there is no evidence of enhancement in a normal brain
- No clinical trial of any amylin receptor antagonist has ever been registered
- Essentially all work comes from one laboratory
Adverse effects
- No sedation, motor signs or weight loss in mice; no human exposure of any kind