In general, Alzheimer’s disease (AD) exhibits as a neurodegenerative disorder characterized by progressive memory loss and cognitive decline. The neuropathologic hallmarks of AD are extracellular plaques of insoluble amyloid β (Aβ). And intracellular neurofibillary tangles (NFT) composed of hyperphosphorylated tau protein and atrophy of the cerebral cortex. All these pathologic changes begin years before the onset of symptoms.
Multiple lines of evidence support the amyloid cascade hypothesis stating that Aβ accumulation and deposition are the initiating factors for the pathogenesis of AD. The hypothesis puts forward factors such as increased production or decreased clearance of Aβ from the central nervous system (CNS), driving the Aβ accumulation in brain. As a consequence, agents preventing formation of Aβ could have disease-modifying properties for AD. The amyloidogenic processing of APP is initiated by β-site APP cleaving enzyme 1 (BACE1).
BACE1 serves as an aspartyl protease, cloned initially by several groups, that cleaves the N-terminus of Aβ, followed by γ-secretase cleaving the C-terminal end. In this process, BACE1 cleavage is the first and rate-limiting step. Subsequent γ-secretase cleavage results in formation of Aβ species of different lengths, from which Aβ1–40 is the predominant one. The cleavage site for another APP processing enzyme, α-secretase, lies within the Aβ sequence and thus precludes Aβ formation.
Inhibitors of BACE1 prevent the formation of Aβ and would therefore be potential therapeutic agents for AD.
Moreover, Atabecestat (JNJ-54861911) exhibits as the first BACE inhibitor. Herein, we describe the safety and tolerability, and peripheral and central PK and PD characteristics of JNJ-54861911 after dosing. Confirmation of peripheral and central BACE1 inhibition, and as such target engagement of JNJ-54861911, was assessed primarily by Aβ1–40 levels in plasma and cerebrospinal fluid (CSF).
To sum up, Atabecestat (JNJ-54861911) is a potent brain-penetrant and orally active β-site amyloid precursor protein cleaving enzyme 1 (BACE1) inhibitor, achieves robust and high CSF Aβ reduction. Also, Atabecestat (JNJ-54861911) shows tolerated activity and displays a sustained pharmacokinetic (PK) and pharmacodynamic (PD) characteristics. Atabecestat (JNJ-54861911) has the potential for Alzheimer’s Disease treatment.