An amylin analog used as a challenge test for Alzheimer's disease

Abstract

Introduction Preclinical studies demonstrate the potential of amylin in the diagnosis of Alzheimer’s disease (AD). We aimed to lay the foundation for repurposing the amylin analog and a diabetes drug, pramlintide, for AD in humans. Methods We administered a single subcutaneous injection of 60 μg of pramlintide to nondiabetic subjects under fasting conditions. Results None of the participants developed hypoglycemia after the injection of pramlintide. The pramlintide challenge induced a significant surge of amyloid-β peptide and a decrease in total tau in the plasma of AD subjects but not in control participants. The pramlintide injection provoked an increase in interleukin 1 receptor antagonist and a decrease in retinol-binding protein 4, which separates AD subjects from control subjects. Discussion Pramlintide use appeared to be safe in the absence of diabetes. The biomarker changes as a result of the pramlintide challenge, which distinguished AD from control subjects and mild cognitive impairment.

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

“…Our research demonstrated that amylin treatment reduced the amyloid burden in the brain by removing Aβ from the brain in AD mouse models (Zhu et al, 2015). A translational study using human subjects demonstrates that a single injection of pramlintide, an amylin analog, similarly induced a surge of Aβ in plasma in AD patients (Zhu et al, 2017a). Amylin and Aβ have consistently been positively associated in plasma in humans (Qiu et al, 2014), suggesting that the more amylin in blood crossing the BBB, the more Aβ moved out of the brain into the blood.…”

Pramlintide: The Effects of a Single Drug Injection on Blood Phosphatidylcholine Profile for Alzheimer’s Disease

“…Our recent study shows that pramlintide challenge induces increases in Aβ and a decrease in t-tau levels in AD patients [11]. This study further demonstrated that a combination of mobilized direct AD biomarkers from the brain into blood [10] and an analysis of signature PC levels in the pramlintide challenge test may be a valuable diagnostic test for AD (Figure 5).…”

“…Using AD mouse models, two independent studies demonstrated that treatment with amylin or its clinical analog, pramlintide, reduced AD pathology in the brain and improved learning and memory [9, 10]. A single peripheral injection of amylin or pramlintide result in the transfer of amyloid-β peptide (Aβ) from the brain into the blood in AD mouse models [10] and AD patients [11]. Because amylin regulates glucose and lipid metabolism [12], pramlintide treatment is likely to influence the phospholipid profile in AD patients, and a test combining a pramlintide challenge and an analysis of phospholipid levels may therefore be useful for diagnosing AD.…”

Amylin in Alzheimer's disease: Pathological peptide or potential treatment?

“…Intraperitoneal injection of amylin increased circulating levels of Aβ in the Tg2576 mouse (increases in both Aβ1–40 and Aβ1–42 in serum), the 5XFAD mouse (increased serum Aβ1–42), and the Dutch APP mouse (increased serum Aβ1–40) (Mohamed et al, 2017; Zhu et al, 2015). Of potential clinical relevance, similar effects were observed after subcutaneous pramlintide administration in human patients with AD, who displayed increased plasma Aβ1–40 after acute pramlintide treatment (Zhu et al, 2017a). The mechanisms by which amylin-induced efflux of Aβ occurs are not completely understood, but may involve LRP1, a protein involved in Aβ transport.…”