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IC‐P‐082: TAU AND ALPHA‐SYNUCLEIN SELECTIVE BINDING COMPOUNDS DERIVED FROM APRINOIA THERAPEUTIC'S PM‐PBB3 BINDING‐SITE FOCUSED COMPOUND COLLECTION
Author(s) -
Tempest Paul,
Ono Maiko,
Higuchi Makogto,
Shimada Hitoshi,
Suhara Tetsuya,
Tai Chin Yin,
Tamagnan Gilles,
Carroll Vincent,
Alagille David,
Barret Olivier,
Marek Ken,
Jang Ming-Kuei
Publication year - 2018
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2018.06.2146
Subject(s) - progressive supranuclear palsy , alpha synuclein , chemistry , neuroscience , binding site , medicine , psychology , biochemistry , parkinson's disease , pathology , disease
AD and wild-type (WT) littermates (males; n1⁄410/group) byMorris Water Maze (MWM). MWM tests were performed at 12 months of age (when HIP rats develop amylin pathology) and 16 months of age (when AD rats have fully developed AD-like pathology). Brain structure in each rat was assessed by T2-weighted MRI (7T; TR: 3000ms; TE: 24ms). At 12 and 16 months of age, n1⁄45 animals from each group were investigated for cellular markers of the blood-brain barrier (BBB) injury and interaction of amylin with Ab. Results: Amylin dyshomeostasis greatly accelerated brain structural abnormalities in ADHIP rats, as demonstrated by enlarged ventricles and brain atrophy. Compared to WT controls, ADHIP, AD and HIP rats have impaired learning (P<0.05). The latency to platform is significantly longer for ADHIP rats compared to AD rats (P1⁄40.03) indicating a faster decline of brain function in ADHIP rats. Staining of brain sections using cellular markers of astrocytes (GFAP), microglia/macrophages (CD11b), microglia (Iba1), reactive microglia (CD68), and select microglial phenotype markers (IL-1b and TNFa as M1 markers; Arg1 and CD36 as M2 markers) demonstrates BBB breakdown in ADHIP and HIP rats. Cerebral vascular amylin deposits, microhemorrhages, loss of endothelial cell coverage in capillaries and white matter rarefaction were also seen in ADHIP and HIP, but not AD and WT rats. At 16 months of age, the latency to platform was similar for ADHIP and AD rats. Histologic analysis revealed mixed Ab-amylin plaques in brains of ADHIP rats. Conclusions:Systemic amylin dyshomeostasis and subsequent accumulation of oligomerized amylin in the brain greatly accelerates AD-like pathology by provoking BBB breakdown and Ab-amylin deposition in the brain parenchyma.