Activity-dependent neuroprotective protein snippet NAP reduces tau hyperphosphorylation and enhances learning in a novel transgenic mouse model.
ABSTRACT Activity-dependent neuroprotective protein (ADNP) differentially interacts with chromatin to regulate essential genes. Because complete ADNP deficiency is embryonic lethal, the outcome of partial ADNP deficiency was examined. ADNP(+/-) mice exhibited cognitive deficits, significant increases in phosphorylated tau, tangle-like structures, and neurodegeneration compared with ADNP(+/+) mice. Increased tau hyperphosphorylation is known to cause memory impairments in neurodegenerative diseases associated with tauopathies, including the most prevalent Alzheimer's disease. The current results suggest that ADNP is an essential protein for brain function and plays a role in normal cognitive performance. ADNP-deficient mice offer an ideal paradigm for evaluation of cognitive enhancers. NAP (NAPVSIPQ) is a peptide derived from ADNP that interacts with microtubules and provides potent neuroprotection. NAP treatment partially ameliorated cognitive deficits and reduced tau hyperphosphorylation in the ADNP(+/-) mice. NAP is currently in phase II clinical trials assessing effects on mild cognitive impairment.
- SourceAvailable from: Tomohiro Chiba03/2013: pages 181-225; , ISBN: 978-953-51-1088-0
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ABSTRACT: 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.Molecular Psychiatry advance online publication, 16 April 2013; doi:10.1038/mp.2013.32.Molecular psychiatry 04/2013; · 15.05 Impact Factor
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ABSTRACT: Neurodegenerative diseases are characterized by the progressive loss of neurons and glial cells in the central nervous system correlated to their symptoms. Among these neurodegenerative diseases are Alzheimer's disease (AD) and amyotrophic lateral sclerosis (ALS). Neurodegeneration is mostly restricted to specific neuronal populations: cholinergic neurons in AD and motoneurons in ALS. The demonstration that the onset and progression of neurodegenerative diseases in models of transgenic mice, in particular, is delayed or improved by the application of neurotrophic factors and derived peptides from neurotrophic factors has emphasized their importance in neurorestoration. A range of neurotrophic factors and growth peptide factors derived from activity-dependent neurotrophic factor/activity-dependent neuroprotective protein has been suggested to restore neuronal function, improve behavioral deficits and prolong the survival in animal models. In this review article, we focus on the role of trophic peptides in the improvement of AD and ALS. An understanding of the molecular pathways involved with trophic peptides in these neurodegenerative diseases may shed light on potential therapies.Open journal of neuroscience. 04/2013; 3.