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

Abstract

Studies suggest that a single injection of pramlintide, an amylin analog, induces changes in Alzheimer’s disease (AD) biomarkers in the blood of AD mouse models and AD patients. The aim of this study was to examine whether a pramlintide challenge combined with a phosphatidylcholine (PC) profile diagnoses of AD and mild cognitive impairment (MCI) better than PC alone. Non-diabetic subjects with cognitive status were administered a single subcutaneous injection of 60 mcg of pramlintide under fasting condition. A total of 71 PCs, amyloid-β peptide (Aβ) and total tau (t-tau) in plasma at different time points were measured and treated as individual variables. A single injection of pramlintide altered the levels of 7 PCs in the blood, while a pramlintide injection plus food modulated the levels of 10 PCs in the blood (p < 0.05). The levels of 2 PCs in MCI and 12 PCs in AD in the pramlintide challenge were significantly lower than the ones in controls. We found that while some PCs were associated with only Aβ levels, other PCs were associated with both Aβ and t-tau levels. A receiver operating characteristic (ROC) analysis of the PCs was combined with the Aβ and t-tau data to produce an area under the curve predictive value of 0.9799 between MCI subjects and controls, 0.9794 between AD subjects and controls and 0.9490 between AD and MCI subjects. A combination of AD biomarkers and a group of PCs post a pramlintide challenge may provide a valuable diagnostic and prognostic test for AD and MCI.

Amylin Pharmacology in Alzheimer’s Disease Pathogenesis and Treatment

“…Conversely, Zhu et al (2017) reported that amylin significantly decreased phosphorylated Ser396/Ser 404 Tau (PHF-1) and p25 in 3XFAD mice, compared to controls, thus reducing pathology. Additionally, this study also found that AC253 blockade of AMYR blocked these effects [ 157 ]. However, the relationship between amylin and tau and the impact of amylin receptor agonism or antagonism on tau pathology remains fully explored.…”

“…The most attention-grabbing aspect of amylin research in AD is the directly conflicting reports that amylin agonism and antagonism are therapeutically beneficial in the disease. To this end, studies support both a ‘gain-of-toxic-function’ by amylin aggregation, either by providing a seed for Aβ [ 55 , 56 ], or driving toxicity through its receptor [ 159 , 162 ], as well as a beneficial effect of amylin or analog therapy [ 155 - 157 , 164 ]. The latter supports the hypothesis that aggregation-mediated depletion of free amylin may lead to a “loss of native function” , an aspect that is supported by negative correlations between free amylin and AD in human studies [ 149 , 155 ] (Fig.…”

“…Additional studies have confirmed these findings in other mouse AD-mouse models. Both human amylin and pramlintide, in 5XFAD and Tg2576 mice, improved Y maze and MWM performance [ 156 ], an aspect that was demonstrated to be AMYR dependent [ 157 ].…”

“…In vivo work in the 5XFAD mouse showed lower expression of ionized calcium-binding adaptor molecule 1 (IBA-1) and diminished microglial activation. Importantly, co-administration of AC253 + amylin blocked this reduction of neuroinflammation, suggesting that AMYR activation may mediate anti-inflammatory pathways [ 157 ]. Together, while the data are conflicting, the presence of amylin AMYR in microglia suggests a direct inflammation regulatory role for this peptide that should be further explored.…”