NAP (davunetide) rescues neuronal dysfunction in a Drosophila model of tauopathy

• Published in: Molecular psychiatry Vol. 18; no. 7; pp. 834 - 842
• Main Authors: Quraishe, S, Cowan, C M, Mudher, A
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.07.2013; Nature Publishing Group
• Subjects: 631/80/128/1653; 692/699/375/132/1283; 692/700/565/1436; Adult and adolescent clinical studies; Alzheimer's disease; Animals; Axonal transport; Axonal Transport - drug effects; Behavioral Sciences; Biological and medical sciences; Biological Psychology; Central nervous system agents; Degeneration; Degenerative and inherited degenerative diseases of the nervous system. Leukodystrophies. Prion diseases; Disease Models, Animal; Dosage and administration; Drosophila; Food; Insects; Life sciences; Medical sciences; Medicine; Medicine & Public Health; Microtubules - drug effects; Microtubules - metabolism; Motor Activity - drug effects; Nervous system; Neurodegeneration; Neurology; Neurons; Neurons - drug effects; Neurons - metabolism; Neurosciences; Oligopeptides - pharmacology; Oligopeptides - therapeutic use; Organic mental disorders. Neuropsychology; Original; original-article; Permeability; Pharmacotherapy; Phosphorylation - drug effects; Proteins; Psychiatry; Psychology. Psychoanalysis. Psychiatry; Psychopathology. Psychiatry; Synapses - drug effects; tau Proteins - genetics; tau Proteins - metabolism; tau Proteins - toxicity; Tauopathies - drug therapy; Tauopathies - genetics; Tauopathies - metabolism; Toxicity; United Kingdom > UK; United States > US; axonal transport; NAP (davunetide); microtubules; Alzheimer’s disease; Nervous system diseases; Alzheimer disease; Insecta; Drosophila; Biological transport; Davunetide; Neuroprotective agent; Drosophilidae; Cerebral disorder; Arthropoda; Central nervous system disease; Cytoskeleton; Degenerative disease; Models; Microtubule; Invertebrata; Nap; Alzheimer's disease; Diptera
• ISSN: 1359-4184; 1476-5578
• DOI: 10.1038/mp.2013.32

Alzheimer’s disease (AD) is a devastating neurodegenerative disease causing irreversible cognitive decline in the elderly. There is no disease-modifying therapy for this condition and the mechanisms underpinning neuronal dysfunction and neurodegeneration are unclear. Compromised cytoskeletal integrity within neurons is reported in AD. This is believed to result from loss-of-function of the microtubule-associated protein tau, which becomes hyper-phosphorylated and deposits into neurofibrillary tangles in AD. We have developed a Drosophila model of tauopathy in which abnormal human tau mediates neuronal dysfunction characterised by microtubule destabilisation, axonal transport disruption, synaptic defects and behavioural impairments. Here we show that a microtubule-stabilising drug, NAPVSIPQ (NAP), prevents as well as reverses these phenotypes even after they have become established. Moreover, it does not alter abnormal tau levels indicating that it by-passes toxic tau altogether. Thus, microtubule stabilisation is a disease-modifying therapeutic strategy protecting against tau-mediated neuronal dysfunction, which holds great promise for tauopathies like AD.