The paradigm of amyloid precursor protein in amyotrophic lateral sclerosis: The potential role of the 682 YENPTY 687 motif

Neurodegenerative diseases are characterized by the progressive decline of neuronal function in several brain areas, and are always associated with cognitive, psychiatric, or motor deficits due to the atrophy of certain neuronal populations. Most neurodegenerative diseases share common pathological mechanisms, such as neurotoxic protein misfolding, oxidative stress, and impairment of autophagy machinery. Amyotrophic lateral sclerosis (ALS) is one of the most common adult-onset motor neuron disorders worldwide. It is clinically characterized by the selective and progressive loss of motor neurons in the motor cortex, brain stem, and spinal cord, ultimately leading to muscle atrophy and rapidly progressive paralysis. Multiple recent studies have indicated that the amyloid precursor protein (APP) and its proteolytic fragments are not only drivers of Alzheimer's disease (AD) but also one of the earliest signatures in ALS, preceding or anticipating neuromuscular junction instability and denervation. Indeed, altered levels of APP peptides have been found in the brain, muscles, skin, and cerebrospinal fluid of ALS patients. In this short review, we discuss the nature and extent of research evidence on the role of APP peptides in ALS, focusing on the intracellular C-terminal peptide and its regulatory motif 682YENPTY687, with the overall aim of providing new frameworks and perspectives for intervention and identifying key questions for future investigations.