Abstract:

Alzheimer’s disease (AD) is a progressive, neurodegenerative disease characterized clinically by gradual cognitive decline including loss of memory, orientation and reasoning, and is pathologically characterized by accumulation of neurofibrillary tangles and amyloid plaques in the brain. The rate of growth of these amyloid plaques differs throughout neocortical and hippocampal regions, and are formed from oligomers of amyloid-β (Aβ) in the intracellular and extracellular space. Aβ is the result of proteolysis of amyloid precursor protein (APP) by β and γ-secretase enzymes. The accumulation of Aβ oligomers becomes progressively toxic and triggers the start of neurodegenerative processes. Here we discuss the role of Lingo-1, or LERN1 (leucine-rich repeat neuronal protein 1) in this process, a transmembrane protein which is highly abundant in the brain and is implicated in numerous neurodegenerative disorders, and demonstrate reasons suggesting its potential for a role in future AD therapy. It appears that Lingo-1 plays a critical role in the AD pathophysiology by both favoring the β-cleavage of APP and the generation of Aβ fragment, but also by the activation of key molecular signaling pathways leading to the inhibition of neuronal outgrowth and survival. An antibody targeting Lingo-1 (BIIB033 produced by Biogen®), has been engineered to be able to cross the blood brain barrier and to antagonize Lingo-1 within the central nervous system. This Lingo-1 antagonist is currently in phase II clinical trials for treating multiple sclerosis and may prove to be a promising treatment option for future AD therapies.