Oral Amylin Treatment Reduces the Pathological Cascade of Alzheimer's Disease in a Mouse Model.

Intraperitoneal injection of amylin or its analog reduces Alzheimer's disease (AD) pathology in the brains. However, self-injecting amylin analogs is difficult for patients due to cognitive deficits. This work aims to study the effects of amylin on the brain could be achieved by oral delivery as some study reported that amylin receptor may be present in the gastrointestinal tract. A 6-week course of oral amylin treatment reduced components of AD pathology, including the levels of amyloid-ß, phosphorylated tau, and ionized calcium binding adaptor molecule 1. The treatment reduced active forms of cyclin-dependent kinase 5. Oral amylin treatment led to improvements in social deficit in AD mouse. Using immunofluorescence, we observed the amylin receptor complexed with the calcitonin receptor and receptor activity-modifying proteins in the enteric neurons. The study suggests the potential of the oral delivery of amylin analogs for the treatment of AD and other neurodegenerative diseases through enteric neurons.

Characterization of the effects of calcitonin gene-related peptide receptor antagonist for Alzheimer's disease.

Calcitonin gene-related peptide (cGRP) receptor antagonists effectively treat migraine through reducing neuroinflammation, vasoconstriction and possibly neruogenesis. Since neuroinflammation is also involved in the pathogenesis of Alzheimer's diseases (AD), we hypothesized and tested if a cGRP receptor antagonist, BIBN 4096 BS (BIBN), has effects on AD pathology. Using an AD mouse model, 5XFAD, with different ages, here we report that the BIBN treatment significantly increased the brain expression of PSD95, a postsynaptic protein, in both young and old AD mice. In parallel, BIBN improved learning and memory in the behavior test in the young, but not old, AD mice. The BIBN treatment reduced α-synuclein aggregation in both young and old AD mice. BIBN significantly decreased neuroinflammatory markers of ionized calcium binding adapter molecules-1 (Iba-1) and the p38 MAPK and NFκB signaling pathways in young, but not old, AD mice. The treatment also reduced the accumulation of amyloid-ß (Aß), and decreased tau phosphorylation through the pathway of CDK5/p25 in young mice only. Our study provides the evidence and suggests that the cGRP antagonists might be a therapeutic target to attenuate the pathological cascade and delay cognitive decline of AD in humans.