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 in vivo, we overexpressed NMNAT3 in two different models: a Drosophila model overexpressing APP and PS1 in developing photoreceptors, and the 3xTg-AD mouse, in which NMNAT3 was expressed in forebrain neurons and which accumulates neurofibrillary tangles and plaques in the hippocampus and cortex. When expressed in the Drosophila eye, APP accumulated in a location- and time-dependent manner, and co-expression of NMNAT3 decreased the total number of aggregates. When expressed in the mouse brain, NMNAT3 did not affect amyloid plaque number or volume; nonetheless, it altered APP processing, leading to the accumulation of oligomers and soluble C-terminal fragments. We conclude that the effects of NMNAT3 on APP differ between models, likely due to differences in access to the sites of protein aggregation and the neuronal environments between flies and mice.
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