A recent scientific-report is scorching news headlines, for very obvious reasons. This study claims, for the first time, that boosting levels of a single 'master regulator' of brain signaling, (EphB2) one effectively resolves symptoms of the dreaded Alzheimer's disease (AD), at least for now, in mice. Although achieving similar results in humans might still be a long way off, yet findings of the study have raised hope of an entirely new approach to tackling this debilitating disease in humans.
Alzheimer's diesease: (AD)—also called senile dementia of the Alzheimer type, primary degenerative dementia of the Alzheimer's type, or simply Alzheimer's—is the most common form of dementia. As the disease advances, symptoms include confusion, irritability and aggression, mood swings, language breakdown, long-term memory loss and the general withdrawal of the sufferer as their senses decline. This degenerative disease was first described by the German psychiatrist and neuropathologist Alois Alzheimer, in 1906.
I dont have recent data, but in 2006 alone, there were 26.6 million sufferers worldwide. And, AD is predicted to affect 1 in 85 people globally by 2050. The disease course is generally characterised with progressive patterns of cognitive and functional impairments.
Mechanism: AD has been identified as a protein misfolding disease (proteopathy), caused by accumulation of abnormally folded A-beta and tau proteins in the brain. Plaques are made up of small peptides, 39–43 amino acids in length, called beta-amyloid. Beta-amyloid is a fragment from a larger transmembrane protein called amyloid precursor protein (APP). APP is critical to neuron growth, survival and post-injury repair. In AD, APP gets divided into smaller fragments by enzymes through proteolysis. One of these fragments gives rise to fibrils of beta-amyloid, which form clumps that deposit outside neurons in dense formations known as senile/amyloid plaques.
AD is also caused due to abnormal aggregation of the tau protein. Every neuron has a cytoskeleton, an internal support structure partly made up of structures called microtubules. These microtubules act like tracks, guiding nutrients and molecules from the body of the cell to the ends of the axon and back. A protein called tau stabilizes the microtubules when phosphorylated, and is therefore called a microtubule-associated protein. In AD, tau undergoes chemical changes, becoming hyperphosphorylated; it then begins to pair with other threads, creating neurofibrillary tangles and disintegrating the neuron's transport system.
About EphB2 (wiki): Members of the Eph family of receptor tyrosine kinases control many aspects of cellular interactions during development, including axon guidance in neurons. Hence, EphB2 acts both as a receptor and an enzyme in a Neuron. EphB2 also regulates postnatal synaptic function in the mammalian CNS. A number of Eph receptors and their ligands (Ephrins) continue to be expressed following the period of primary CNS innervation. It is considered rather important for dendritic maturation and critical for synaptic functions. Incidentally, brain levels of EphB2 are decreased in AD.
Outline of the study: Scientists at the Gladstone Institute of Neurological Disease (GIND) in San Francisco used a genetically engineered mouse model of AD, which simulates the disease (AD) and has abnormally low levels of EphB2 in memory centers of the brain. As it turned out during the course of the study, improving EphB2 levels in these mice by gene therapy completely fixed their memory problems.
mice used for the study [hAPP-mice]: Human amyloid precursor protein (hAPP) transgenic mice with high brain levels of amyloid-beta oligomers have reduced hippocampal levels of tyrosine-phosphorylated NMDA receptors (a glutamate receptor, is the predominant molecular device for controlling synaptic plasticity and memory function in neurons) and key components of NMDA-receptor-dependent signalling pathways. Very significantly, Hippocampal-levels of the receptor tyrosine kinase EphB2 are depleted in both AD patients and hAPP mice, which makes it an apt model-system choice.
Crucial Experiments / Observations: Investigators used gene therapy to experimentally alter EphB2 levels in memory centers of mice.
Reducing EphB2 levels using sh-RNA in normal healthy mice disrupted neurotransmission, impaired synaptic plasticity and reduced synaptic strength. Overall, it gave them memory problems similar to those seen in AD. This finding suggests that the reduced EphB2 levels in AD brains directly contribute to the memory problems that characterize the AD-condition.
Having achieved this, the cricitcal question of course now, was to assess whether normalizing EphB2 levels could fix memory problems caused by amyloid proteins.
To determine if increasing EphB2 expression in the dentate gyrus of hAPP mice reverses memory deficits, folks used a lentivirus expressing EphB2 (gene therapy method). Indeed, increasing dentate gyrus EphB2 levels reversed LTP deficits in two independent cohorts of hAPP mice. Dumping EphB2 proteins rescued synaptic functions and ameliorated cognitive (Spatial learning and memory) deficits in hAPP mice.
Reducing EphB2 levels using sh-RNA in normal healthy mice disrupted neurotransmission, impaired synaptic plasticity and reduced synaptic strength. Overall, it gave them memory problems similar to those seen in AD. This finding suggests that the reduced EphB2 levels in AD brains directly contribute to the memory problems that characterize the AD-condition.
Having achieved this, the cricitcal question of course now, was to assess whether normalizing EphB2 levels could fix memory problems caused by amyloid proteins.
To determine if increasing EphB2 expression in the dentate gyrus of hAPP mice reverses memory deficits, folks used a lentivirus expressing EphB2 (gene therapy method). Indeed, increasing dentate gyrus EphB2 levels reversed LTP deficits in two independent cohorts of hAPP mice. Dumping EphB2 proteins rescued synaptic functions and ameliorated cognitive (Spatial learning and memory) deficits in hAPP mice.
This study shows that EphB2 depletion contributes to amyloid-b-induced neuronal deficits and cognitive dysfunction. It pointedly shows that EphB2 impairment is necessary and sufficient to elicit impaired Long term Potentiation (LTP) and memory. Importantly, they showed that increasing neuronal EphB2 levels in hAPP mice reversed these deficits.
Of course, this work immediately doesn't provide medical advice, diagnosis or treatment for humans but could certainly pave the way for follow-up studies and eventual possible remedies for scores of human patients.
This study also stirs the already-sizzling debate of whether there could be potential "Master-Genes" in our system. Of course, with a growing acceptance for Network-models of signaling, one has to still work out the various possible targets and nodes (sensitive check points of control, where subsets of the signaling module meet) for a better understanding of the signaling pathway leading to AD.
This study also stirs the already-sizzling debate of whether there could be potential "Master-Genes" in our system. Of course, with a growing acceptance for Network-models of signaling, one has to still work out the various possible targets and nodes (sensitive check points of control, where subsets of the signaling module meet) for a better understanding of the signaling pathway leading to AD.
References:
* Reversing EphB2 depletion rescues cognitive functions in Alzheimer model. Nature, November 2010; DOI: 10.1038/nature09635. Moustapha Cissé, Brian Halabisky, Julie Harris, Nino Devidze, Dena B. Dubal, Binggui Sun, Anna Orr, Gregor Lotz, Daniel H. Kim, Patricia Hamto, Kaitlyn Ho, Gui-Qiu Yu and Lennart Mucke.
* The Receptor Tyrosine Kinase EphB2 Regulates NMDA-Dependent Synaptic Function. Neuron, Vol. 32, 1041–1056, December 20, 2001. Jeffrey T. Henderson, John Georgiou, Zhenping Jia, Jennifer Robertson, Sabine Elowe, John C. Roder,and Tony Pawson.
* The Receptor Tyrosine Kinase EphB2 Regulates NMDA-Dependent Synaptic Function. Neuron, Vol. 32, 1041–1056, December 20, 2001. Jeffrey T. Henderson, John Georgiou, Zhenping Jia, Jennifer Robertson, Sabine Elowe, John C. Roder,and Tony Pawson.
* An Alzheimer's cure? Boosting levels of a 'master regulator' of brain signaling could resolve symptoms [Source]
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