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    How Presenilin Mutations Destroy Memories
    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 suggests that the abnormal accumulation of amyloid beta proteins in Alzheimer’s disease is directly responsible for the memory loss (1). It is generally accepted that amyloid beta proteins can interact with amyloid-beta receptors on the surface of neurons, and that the interaction can trigger the destruction of neuronal synapses (connections between neurons) that encode memories. The destruction occurs when the amyloid-beta receptors activate enzymes to break down the supportive structure (a cable network known as the cytoskeleton) inside synapses (1). Indeed, strategies to block amyloid-beta receptors can help prevent the breakdown of synapses and to slow the onset of memory loss in AD (1).

    Further adding to this story, a recent study published in Neuron (2) shows that presenilin- a protein mutated in AD- can also contribute to memory loss. In this study, Dr. Ilya Bezprozvanny and colleagues at the UT Southwestern Medical Center in Dallas, Texas, discovered that mutations in the presenilin gene can impair sustained calcium signals that are crucial for maintaining the integrity of synapses and the memories they encode.

    Presenilin is only recently shown to work as a calcium leak channel in the neuron's internal storage compartment known as the endoplasmic reticulum (ER) (3). The ER is normally the home of a calcium sensor (STIM) that is activated in response to low calcium levels in the ER. By leaking calcium out from the ER, presenilin’s main role is to create a calcium environment in the ER to favor STIM activation. The activated STIM can in turn stimulate store-operated calcium channels (SOCs) that are responsible for generating sustained calcium signals in the synapse. The sustained calcium signals are required for activating calcium-responsive enzyme (CAMKII) necessary to stabilize synapses.

    In Alzheimer’s disease, Bezprozvanny shows that presenilin mutation can impair STIM activation, and can sabotage the sustained calcium signals needed to stabilize synapses and the memories they encode. To show this, 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. Bezprozvanny further demonstrate that the overexpression of activated STIM (the ER calcium sensor) can help restore synaptic stability in transgenic mouse models of AD in which presenilin is mutated.

    The study here provides the first crucial link explaining how presenilin mutation, a hallmark in AD brains, may be responsible for memory loss in AD. The finding may also point to a promising gene therapy to prevent memory loss in patients with Alzheimer’s disease.

    References:

    1. Kim et al. Science. 341, 1399-404, 2013

    2. Sun et al. Neuron. 82, 79–93, 2014.

    3. Tu et al. Cell. 126, 981-93, 2006.