Mitochondrial NMNAT3 reduces amyloid aggregates in

Alzheimer's disease is a progressive neurological disorder characterized by two main neuropathological hallmarks: neurofibrillary tangles and amyloid plaques. Both are protein aggregates, composed mainly of hyperphosphorylated Tau and the amyloid fragment Aβ, respectively. NMNAT (Nicotinamide mononucleotide adenylyltransferase) is an endogenous enzyme involved in the conversion of NMN to NAD. It is known for its neuroprotective functions, particularly against axonal degeneration. We have previously shown that different isoforms of NMNAT can protect cells from neurotoxic stress caused by protein aggregates by acting as chaperones. Accordingly, the mitochondrial-localized isoform NMNAT3 exhibits potent chaperone activity, which antagonizes the aggregation of a wide spectrum of pathological amyloid client proteins in culture, including Tau and amyloid beta. Although mostly cytosolic, Aβ has also been detected in mitochondria and mitochondrial membranes. To investigate whether NMNAT3 could serve as a neuroprotective factor in amyloid pathology