- Alzheimer’s disease is characterized by the loss of synapses, the sites where nerve cells communicate with each other, in brain regions involved in cognitive function.
- Studies have shown that short chains of the beta-amyloid protein, called oligomers, can cause a dysfunction of synapses and their loss.
- A new study conducted using nerve cells from rodent brains has found a novel pathway through which beta-amyloid causes the loss of synapses.
- Mdm2, an enzyme belonging to this pathway, can be inhibited to prevent the loss of synapses and, thus, could be a target for the development of treatments for Alzheimer’s disease.
An aging population and the lack of effective treatments have made Alzheimer’s disease a global health crisis. Several Alzheimer’s disease treatments, including
However, therapies targeting molecules that mediate the toxic effects of beta-amyloid could be more effective in the treatment of Alzheimer’s disease.
A new study published in the journal eNeuro has uncovered a novel pathway through which beta-amyloid oligomers could cause a loss of synapses in brain regions impacted by Alzheimer’s disease.
The study also identified an enzyme in nerve cells called Mdm2 in this pathway that was necessary for beta-amyloid-mediated loss of synapses, which are the links between brain cells.
These results suggest that molecules such as Mdm2 in this novel pathway could be targeted for the treatment of Alzheimer’s disease.
Study author, Dr. Mark Dell’Acqua, a professor at the University of Colorado School of Medicine, told Medical News Today that, “[w]hile this is an early-stage discovery in a model system, it does give us a new lead to pursue in development of therapeutics to prevent neuronal synaptic dysfunction associated with Alzheimer’s disease.”
“In particular, our findings suggest that inhibitors of the protein Mdm2 that are in clinical trials for cancer could be repurposed to prevent synapse loss and cognitive decline in Alzheimer’s. The next step will be to test Mdm2 inhibitors in rodent models of Alzheimer’s,” added Dr. Dell’Acqua.
Alzheimer’s disease is associated with the accumulation of deposits of the beta-amyloid protein in the brain regions involved in memory and thinking. These regions affected by Azlheimer’s disease include the cerebral cortex and the hippocampus.
The beta-amyloid deposits are formed by the aggregation of repeated units, referred to as monomers. Each beta-amyloid monomer assembles into short chains called oligomers, which then assemble into fibrils. These fibrils eventually aggregate to form insoluble deposits called plaques.
Although researchers previously hypothesized that beta-amyloid deposits underlied the development of Alzheimer’s disease, beta-amyloid oligomers are now
Alzheimer’s disease is characterized by the loss of synapses, which are specialized regions where one neuron interacts with another by releasing chemical messengers called neurotransmitters.
Beta-amyloid oligomers cause a loss of synapses in regions involved in cognitive function, and the extent of synaptic loss is associated with cognitive decline.
The presynaptic neuron releases neurotransmitters that bind to the receptors on the postsynaptic neuron. The binding of the neurotransmitter to the receptor facilitates the generation of an electrical impulse in the postsynaptic neuron in the case of an excitatory synapse but prevents the generation of such an impulse at an inhibitory synapse.
The components of an excitatory synapse on the postsynaptic neurons are typically present on specialized protrusions called spines. These spines are typically found on slender, branch-like neuronal appendages called dendrites that receive excitatory input.
The plasticity of synapses, involving their strengthening or weakening, underlies processes such as learning and memory. Specifically, the acquisition of new memories involves a type of synaptic plasticity known as
Long-term potentiation involves the strengthening of synapses, which allows the same stimulus from the presynaptic neuron to produce a larger response from the postsynaptic neuron.
In contrast, the extinction or loss of memories involves the weakening of the synapse in a process called
Long-term potentiation is associated with the increase in the number of spines, whereas long-term depression is associated with the loss of spines. Experiments have shown that exposure of the hippocampus, a brain region involved in memory, to beta-amyloid oligomers promotes long-term depression while impairing long-term potentiation.
The weakening of synapses due to beta-amyloid exposure is accompanied by the loss of spines. Such a loss of spines in brain regions involved in cognition serves as a marker for the dysfunction of excitatory synapses in Alzheimer’s disease.
Glutamate is the most abundant excitatory neurotransmitter in the brain. Upon its release by the presynaptic neuron, glutamate binds to receptors on the postsynaptic neuron, increasing its likelihood of firing.
These glutamate receptors include the N-methyl-d-aspartate (NMDA) receptor and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor. The NMDA and AMPA receptors consist of an ion channel or pore that allows the exchange of sodium and potassium ions upon their activation.
The excitation of the postsynaptic neuron involves the transmission of a nerve impulse due to the entry of sodium ions through the glutamate receptors. In addition to sodium ions, the NMDA receptor and calcium-permeable AMPA (CP-AMPA) receptors, a subtype of AMPA receptors, also allow the entry of calcium ions.
The release of glutamate initially activates the AMPA receptor, facilitating the entry of sodium ions and the excitation of the postsynaptic neuron. When sufficient sodium ions enter the postsynaptic neuron, the magnesium ion that blocks the NMDA receptor is dislodged and allows calcium ions to enter the postsynaptic neuron.
This entry of calcium ions via the NMDA receptor is essential for both long-term potentiation and long-term depression. The entry of high levels of calcium ions during long-term potentiation helps to recruit more AMPA receptors to the surface of the postsynaptic neuron to strengthen the synapse.
In contrast, the entry of a low level of calcium ions facilitates the removal of AMPA receptors from the synapse during long-term depression.
Previous studies have shown that beta-amyloid causes loss of synapses and long-term depression through its action of the NMDA receptor. Beta-amyloid oligomers impair the entry of calcium ions via the NMDA receptor to contribute to the loss of synapses.
In the present study, the researchers used dissociated neurons from the hippocampus of rodents to further examine the effects of beta-amyloid oligomers on excitatory synapses.
The researchers who conducted the present study found that blocking the entry of calcium ions through the NMDA receptors did not prevent synaptic loss. Instead, beta-amyloid oligomers caused synaptic loss by inducing a change in the shape of the NMDA receptor.
However, the entry of calcium ions through the calcium permeable-AMPA (CP-AMPA) receptors was necessary for the beta-amyloid oligomers to eliminate spines. The entry of low levels of calcium through these CP-AMPA receptors activates the calcineurin enzyme, which facilitates long-term depression.
Calcineurin regulates the removal of AMPA receptors from the surface of the postsynaptic neuron to reduce its excitability of the neuron, that is, causes long-term depression and, eventually, leads to spine loss.
The researchers then identified molecules in the pathway downstream of calcineurin that were needed for beta-amyloid-mediated spine loss. Among these molecules included the enzyme Mdm2 which has been previously shown to be involved in mediating spine loss.
Examining the role of Mdm2 in beta-amyloid-mediated spine loss, the researchers found that exposure to beta-amyloid oligomers increased the expression of Mdm2, and the inhibition of Mdm2 prevented spine loss caused by beta-amyloid exposure.
These results suggest that the Mdm2 enzyme may hold promise as a therapeutic target for Alzheimer’s disease.