Yasir, a graduate student in Dr. Cassis' laboratory just published a first-author article...
Han Ly who is a PhD Student in the Pharmacology program won 1rst place in the student category at the poster award competition of the Markesbery Symposium on Aging and Dementia. The event took place last week on November 4th and 5th, here at the University of Kentucky.
Han Ly is currently a student in Dr. Despa' s laboratory. The title of her poster was "Aβ-Amylin Interaction in Brains of Patients with Early-Onset Familial Alzheimer’s Disease"
Please read below the abstract:
Aβ-Amylin Interaction in Brains of Patients with Early-Onset Familial Alzheimer’s Disease
Han Ly1, Savita Sharma1, Miao Liu1, Nirmal Verma1, Jing Chen1, Haining Zhu1, Martin Chow2, Louis B. Hersh2, Claire Troakes3, Matthew Nolan3, Safa Al-Sarraj3, Andrew King3, Istvan Bodi3, Florin Despa1
1 Department of Pharmacology & Nutritional Sciences, 2 Department of Molecular & Cellular Biochemistry, University of Kentucky, Lexington, KY
3 MRC London Neurodegenerative Diseases Brain Bank, Kings College London, London, UK
Objectives: Brain tissues from familial Alzheimer’s disease (F-AD) patients were investigated for possible accumulation of amylin, a pancreatic hormone that is co-secreted with insulin and has similar cytotoxic properties to Aβ.
Methods: Randomized temporal lobe samples from non-diabetic AD patients with presenilin or amyloid precursor protein mutations (F-AD group; <65 yrs old; N=27) and healthy individuals (Ctl group; >75 yrs old; N=12) were tested for amylin deposition by immunohistochemistry, ELISA, western blot and mass spectrometry. Duolink in situ proximity ligation assay (PLA) was employed to verify a possible amylin-Aβ interaction. Tissue pellets were treated with formic acid, freeze dried, then re-suspended in guanidine hydrochloride for further analysis with an amylin antibody by dot blot. To further test the hypothesis that amylin dyshomeostasis exacerbates F-AD pathology by forming mixed amylin-Aβ plaques, we generated a F-AD rat model that overexpresses human amylin in the pancreas (ADHIP). ADHIP rats (N=7; 12 months of age) were compared with age-matched WT rats (N=6), HIP rats (N=4) and F-AD rats (N=7) rats for cognitive performance by novel object recognition and Morris water maze.
Results: Brains of patients with F-AD display amylin immunoreactivity and mixed amylin-Aβ plaques in tissue parenchyma and blood vessels. Interestingly, intraneural amylin deposition appears to correlate with extraneural Aβ accumulation. The presence of mixed amylin-Aβ plaques correlates with an increase (>400% vs. Ctl; P<0.01) of the proximity signal in PLA experiments demonstrating the amylin-Aβ interaction. The levels of soluble amylin as measured by ELISA and western blot were comparable in both F-AD and Ctl groups. Intriguingly, after treatment of brain tissues with formic acid and guanidine hydrochloride, dot blot analysis displayed >300% (P<0.001) higher amylin levels in F-AD brains compared to controls, suggesting that large amylin aggregates fragmented into small oligomers that were recognized by the anti-amylin antibody. The identity of the amylin peptide was further tested by mass spectrometry data, thus convincingly demonstrating that amylin is contained in brain lysates from F-AD patients. Compared to AD rats, the newly generated ADHIP rats show declined recognition memory and impaired learning and spatial memory at an earlier stage of life, indicating that the brain amylin accumulation worsens F-AD pathology.
Conclusions: Blood amylin interacts with Aβ in familial AD and accelerates the disease development and its pathological progression.