Lingo-1: a novel target in therapy for Alzheimer's disease?

Unraveling the causes underlying Alzheimer's disease (AD) is certainly one of the greatest challenges of this century for researchers. With advances in medicine and technology, the world is experiencing a demographic shift towards a growing elderly population. With this increasingly ageing population, the number of individuals being affected by AD is booming. AD has a significant negative impact on the lives of the individuals with the disorder, as well as creating a significant social and economic burden for society. Although major advances have been established in our understanding of the molecular and pathological mechanisms underlying this devastating disorder during the last decades, the causes for neuronal degeneration and its treatment remain elusive. 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. These amyloid plaques have different rates of growth throughout neocortical and hip-pocampal 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 (Hardy and Selkoe, 2002). 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 neurodegener-ative disorders (Andrews and Fernandez-Enright, 2015), and demonstrate reasons suggesting its potential for a role in future AD therapy. Lingo-1, selectively expressed on oligodendrocytes and neurons, is a potent negative modulator of neuronal processes such as neuronal survival, axonal integrity and myelination as well as oligodendrocyte differentiation (Mi et al., 2005). Its action notably involves the Nogo receptor (NgR) as a part of a co-receptor complex, which includes the p75 neurotrophin receptor (p75 NTR) or TNF receptor orphan Y (TROY) (Shao et al., 2005). The resulting trimolecular receptor complex Lingo -1/NgR/p75 or Lingo-1/NgR/TROY activates rho-associated coiled coil-containing protein kinase (RhoA/ROCK) signalling pathways, subsequently initiating a cascade of intracellular molecular events resulting in the collapse of growth cones, preventing further axonal growth and inhibiting myelination (Shao et al., 2005). The inhibition of Lingo-1 induced signalling pathways may be involved in the development of future therapies for neurological disorders such as multiple sclerosis and/or Alzheimer's disease. In addition, the Lingo-1 gene (coding …