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    How Dementia Sabotage Memory Formation And Maintenance
    By Jennifer Wong | April 3rd 2014 05:59 PM | Print | E-mail | Track Comments
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    My column covers the latest primary research discoveries in the life-science discipline. Much of what is reported here are considered discoveries...

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    Memory loss is a debilitating consequence of dementia such as Alzheimer’s disease (AD), an incurable condition contributing to a progressive loss of cognitive function. But what is the cause of memory loss in AD?  Previous work reveals that memory is encoded by molecular and structural changes in synaptic connections between neurons.  

    In AD, the accumulation of amyloid beta can activate specific receptors in the synapses to actively destroy synaptic connections and their encoded memories, specifically by breaking down the actin cytoskeleton that supports the structure of synaptic connections1. Strategies to block amyloid-beta receptors can help prevent the breakdown of synapses and to slow the onset of memory loss in AD1.

    An interesting question that arises is whether AD progression is merely the passive loss of memories caused by the progressive amyloid-beta-mediated destruction of existing synapses.  Considering that AD often contributes to the progressive loss of cognitive function, which impairs the brain’s ability to form and maintain memories; it seems that AD may play a more active role in sabotaging memory formation and maintenance.  However, the precise molecular pathway explaining how AD actively affects memories remains unknown.   

    To address this question, a study published in the April 2014 issue of Neuron2 reveals that presenilin protein mutations characteristic of AD can impair sustained calcium signaling in the synapses, a pathway crucial for the stability and maturation of neuronal synapses. Synapses are the building blocks of memories, and that their stability and maturation underlies memory formation and maintenance.

    The study here shows that active memory formation and maintenance can be sabotaged in AD by disrupting sustained calcium signaling required for synaptic stability and maturation

    This study was conducted by a team of scientists lead by Dr. Ilya Bezprozvanny at the UT Southwestern Medical Center in Dallas, Texas. In this study, Bezprozvanny’s lab used a transgenic mouse model of Alzheimer’s disease (AD), as well as clinical samples from aging and AD brains, to show that disease-associated mutations in the presenilin gene can impair sustained calcium signaling in the synapses. 

    Presenilin is recently shown to work as a calcium leak channel in the endoplasmic reticulum (ER), and presenilin mutations in AD can prevent calcium leakage from the ER, causing the calcium levels in the ER to aberrantly increase3. The study shows that AD-associated increase in ER calcium inactivates the ER calcium sensor (STIM), and prevents the downstream activation of the store-operated calcium channels (SOCs) necessary for sustained calcium signals in the synapse. The loss of sustained calcium signaling via SOCs impairs the activation of a calcium-responsive enzyme (CAMKII) responsible for synaptic stability and maturation, and contributes to memory loss and impaired memory formation in AD. 

    The study provides the first crucial link explaining how presenilin mutation, a hallmark in AD brains, may be responsible for actively impairing memory formation and maintenance in AD.

    By identifying a new molecular mechanism that explains how memory formation and maintenance can be sabotaged in AD, the study here points to a novel drug target to treat AD.  Along this line, Bezprozvanny and colleagues demonstrate that the overexpression of STIM (the ER calcium sensor) can help restore synaptic stability and maturation in transgenic mouse model of AD.

    The preliminary finding points the way to a promising gene therapy to prevent memory loss, and to actively restore memory formation and maintenance, in patients with AD.

    References:

    <!--[if !supportLists]-->1.   <!--[endif]-->Kim et al. Science. 341, 1399-404, 2013

    <!--[if !supportLists]-->2.   <!--[endif]-->Sun et al. Neuron. 82, 79–93, 2014.

    <!--[if !supportLists]-->3.   <!--[endif]-->Tu et al. Cell. 126, 981-93, 2006.