Some researchers have been screaming ‘yes’ to that question for years now and a new study gives more reason to look beyond amyloid.
The Medical Republic is proud to be a mouse-free zone; that is, not only do we keep our office premises largely rodent-free, we do not as a rule report on clinical studies before they reach the human testing phase.
But this is the Back Page, where things get a little loose and we can ignore that rule.
That’s why we’re covering this new Australian study here, even though Alzheimer’s is a lot less funny than a heart attack and there’s nothing frivolous about these implications.
Amyloid may be the defining physical feature of Alzheimer’s, but as a therapeutic target it has proved disappointing over decades, to put it mildly. The tortuous aducanumab saga showed an obvious desperation to push an amyloid-busting drug on to the market, while the subsequent lecanemab and donanemab are more promising but come with many unknowns.
Intuition is never a great guide, but blasting amyloid plaques away just has not had the sort of effects on cognition that you would expect if they were the cause of the syndrome.
Professor Bryce Vissel from St Vincent’s in Sydney, a longstanding sceptic of the amyloid hypothesis, led an international team on a mouse model study that instead targeted the breakdown of synapses that is also associated with Alzheimer’s.
Specifically (more specifically than the Back Page is comfortable with, but here goes), they looked at the GluA2 subunit of the AMPA receptor, where RNA editing is efficient in healthy brains but impaired in Alzheimer’s brains, hypothesising that this contributes to neurodegeneration and memory loss.
The team crossbred J20 Alzheimer’s mice with mice in which unedited GluA2(Q) was eliminated and only GluA2(R) was expressed. These mice showed significantly less dendritic spine loss and neuron loss in the hippocampal CA1 region than regular J20 mice, and they performed better on mazes and other memory tests.
This work fits with the calcium hypothesis of Alzheimer’s – in which calcium regulation is impaired, leading to buildup within cells and then cell death – since GluA2(R) prevents calcium flow through receptors.
They conclude that RNA editing at the Q/R site of GluA2 “acts as an epigenetic switch regulating dendritic spines in health and disease”.
“Having shown that preventing synapse loss offers a way forward to treating Alzheimer’s, our team will now accelerate work towards developing an effective treatment for this devastating disease,” Professor Vissel said in a media statement.
Of course there’s many a slip twixt mouse study and human drug, but the Back Page is barracking for this as a path to an effective treatment. And really hopes they get there in, say, the next 40 years.
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