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S4‐04‐08: Immunotherapy Targeting Pathologically Phosphorylated Tau in a Tauopathy Mouse Model
Author(s) -
Boimel Moran,
Grigoriadis Nikolaos,
Lourbopoulos Athanasios,
Haber Ester,
Abramsky Oded,
Rosenmann Hanna
Publication year - 2009
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.2009.07.135
Subject(s) - tauopathy , immunotherapy , immunohistochemistry , pathological , proinflammatory cytokine , tau protein , neurotoxicity , medicine , neuroinflammation , pathology , tau pathology , immunology , neurodegeneration , inflammation , alzheimer's disease , immune system , disease , toxicity
BACE cleaves the amyloid precursor protein (APP) at the b-secretase site, generating amyloid-b peptides (Ab) and is considered one of the key therapeutic targets for the treatment of Alzheimer’s Disease (AD). Objective: Small molecule BACE inhibitors would be expected to prevent the generation of the Ab peptides and consequently reduce the detrimental effects of Ab toxicity and the formation of amyloid plaques in the brain. One of the major hurdles with BACE inhibitors that plague the pharma industry is achieving in vivo efficacy primarily due to poor brain penetration. Methods: We have identified potent and selective inhibitors of human BACE using rational drug design and X-ray technology. In primary mouse cortical neurons our novel small molecule BACE inhibitors display a dose dependent inhibition of Ab release. Furthermore, we find that our BACE inhibitors inhibit Ab in the brain and plasma of C57BL/6 mice in a concentration-dependent fashion. There is a good correlation between the concentrations required to observe these effects in primary neurons and the free concentration of inhbitor in the brain. Conclusion: Our results suggest that it is possible to overcome brain penetration issues and achieve efficacy in the brain with novel BACE inhibitors. These results strongly support the utility of BACE inhibitors as a technically feasible approach to therapeutic intervention in AD. These results strongly support the utility of BACE inhibitors as a technically feasible approach to therapeutic intervention in AD.