How Amyloid Disrupts Synaptic Plasticity in Alzheimer's Disease

The research community continues to make progress, slow but steady, in understanding the low-level biochemistry of neurodegenerative conditions. It is a very complex area of study. You might compare the research here, focused on amyloid, with results noted yesterday, focused on α-synuclein. The aging of the brain is accompanied by the aggregation of a number of altered proteins, producing solid deposits and a halo of surrounding changes in cell biochemistry that damage or kill brain cells. Beyond that summary, each is very different in mechanisms and outcome. Regardless, the end result is cognitive decline, a disruption of function in the brain. Control of protein aggregation is a major focus of the research community, but achieving any meaningful progress towards that goal has proven to been far more challenging than was hoped when these projects began in earnest.

The accumulation of amyloid peptides in the form of plaques in the brain is one of the primary indicators of Alzheimer's disease. While the harmful effects of amyloid peptide aggregates are well established, the mechanism through which they act on brain cells remains ill-defined. Researchers knew, for instance, that amyloid peptides disrupt synapses - the area of contact and chemical communication between neurons - but did not understand how they did so. Now, new findings have revealed the molecular mechanism that links amyloid aggregates and deficient synaptic function observed in animal models of Alzheimer's disease: peptide oligomers interact with a key enzyme in synaptic balance, thereby preventing its normal mobilization.

The molecule, called CamKII, usually orchestrates synaptic plasticity, an aspect of neuronal adaptability that enables neurons to reinforce their responses to the signals they exchange. Groups of neurons that code for an information to be memorized are connected by synapses, which are themselves under the control of mechanisms of synaptic plasticity. When the connection between two neurons must be reinforced in order to memorize information, for instance during intense stimulation, CamKII is activated and leads to a chain of reactions that strengthen the capacity to transmit messages between these neurons.

Synaptic plasticity is central to memory and learning. Amyloid peptides prevent CamKII from participating in this process of synaptic plasticity, and this blockage eventually leads to the disappearance of the synapse. This discovery could find an application in early phases of Alzheimer's disease when initial cognitive deficiencies are observed, which could be linked to this synaptic malfunction. The goal for researchers now is to continue studying amyloid aggregates, especially by trying to prevent their interaction with CamKII and the loss of synapses observed during the disease.



There was also this Alziheimer's news today:

Exosomes Shown to Be Involved in Spread of Amyloid Beta in Alzheimer's

""Our study demonstrates that it is possible to influence this pathway, and possibly develop drugs that could prevent the spreading. The findings also open up the possibility of diagnosing Alzheimer's disease in new ways, by measuring the exosomes," notes Dr. Hallbeck."

Posted by: Jim at June 14th, 2018 10:39 AM

My thought is that we should find experimental genetic methods to reduce platelet counts in most people, kind of like what the medical community does with statin drugs to reduce LDL cholesterol, and other drugs to reduce triglycerides, etc. Platelets produce the APP (amyloid precursor protein) that is carried by blood vessels to the brain where it is transformed into amyloid beta and causes or strongly contributes to AD. People can get by with no adverse bleeding from low platelet counts of 100K, but most people have platelet counts 3 to 5 times that count number. I have an inherited platelet count of about 105K and have never had any clotting or excessive bleeding problems. I have a PAI gene allele that reduces platelet count by about 50%, and also Gilbert's Syndrome, that also reduces platelet count. Thus, I believe we could genetically use some existing genetic alleles of certain genes to get platelet counts much lower, such that AD rates would also be much lower, and we would not have to clean up the amyloid beta mess that forms in the brain with aging in most people.

Posted by: Biotechy Marcks at June 16th, 2018 9:58 AM

Your idea seemed a little 'out there' to me, but after a bit of literature searching and scanning through some articles, you might be on to something and it perhaps explains some of moderate alcohol consumption's preventative effects for AD (though there could be other possible mechanisms involved).

So... a gin and tonic* a day keeps the AD away? That would be nice :)

*the real quinine stuff; it seems popular now and they even sell a brand at Target

Posted by: CD at June 16th, 2018 2:37 PM

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