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[O4–06–04]: PROTECTIVE EFFECTS OF A BRAIN‐PENETRATING BIOLOGIC TNF‐ALPHA INHIBITOR IN A MOUSE MODEL OF ALZHEIMER's DISEASE
Author(s) -
Chang Rudy,
Knox Jillian,
Chang Jae,
Woods Jeffery,
Derbedrossian Aram,
Vasilevko Vitaly,
Cribbs David H.,
Boado Ruben,
Pardridge William M.,
Sumbria Rachita
Publication year - 2017
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2017.07.451
Subject(s) - neuroinflammation , fusion protein , tumor necrosis factor alpha , medicine , blood–brain barrier , genetically modified mouse , immunology , etanercept , monoclonal antibody , cancer research , pharmacology , transgene , antibody , biology , inflammation , central nervous system , recombinant dna , biochemistry , gene
Background:During the last almost two decades, the vast majority of the therapeutic approaches to treat Alzheimer’s disease (AD) focused mainly on inhibiting neurodegeneration by prevention or clearance of Ab plaques. However, so far results have been disappointing and to date no disease-modifying drug has been approved for the treatment of AD. Herein, we describe a novel therapeutic strategy that focuses on helping the brain’s self-repair attempt during the period of synaptic compensation by boosting the neurotrophic environment with a neurogenic/neurotrophic peptidergic compound (P021). Methods:P021 was administered in diet at 3 months, i.e. during the period of synaptic compensation and continued till 21 months in 3xTg-AD, a transgenic mouse model of AD in which APP swe and tau P301L are overexpressed in PS1 M146V knock-in mice. The 3xTg-AD mice and WT mice treated identically but with vehicle only diet served as controls. The effects of P021 on neurogenesis, dendritic and synaptic markers, tau and Ab pathologies were studied both immunohistochemically and by Western blots, neurodegeneration was studied using Fluorojade C staining, and cognitive performance was studied by assessing spatial reference memory using the Morris Water Maze task, short-term spatial memory by the Novel Object location task and episodic memory with Novel Object Recognition task. Results: We found that P021 treatment was able to rescue dendritic and synaptic deficits, boost neurogenesis, prevent neurodegeneration, Ab and tau pathologies, rescue cognitive impairment in 3xTg-AD mice and markedly reduce mortality rate. Conclusions: These findings for the 1 time show that the availability of appropriate neurotrophic support during the period of synaptic compensation with a neurotrophic compound that targets neurogenesis and synaptic plasticity can be efficient in prevention of Alzheimer’s changes, suggesting that improving the health of the neuronal network can prevent AD and that P021 is a promising neurotrophic compound for this purpose.