Nine out of ten cases of inherited early-onset Alzheimer’s disease trace back to mutations in presenilin 1 or 2, proteins in neurons that help form and maintain memories. While mice with presenilin mutations follow the same progression as human Alzheimer’s patients, with memory loss, compromised ability to learn, and dementia, the exact molecular effects of these mutations have remained a mystery.
To solve this puzzle, Jie Shen, HMS associate professor of neurology at Brigham and Women’s Hospital, approached the problem with a painstaking genetic dissection of the workings of presenilin on both the sending and receiving sides of neural synapses, the junctions where signals are passed between nerve cells. She found that presenilin defects quash the release of neurotransmitters from presynaptic neurons, but have no effect on the transmission of synaptic signals in postsynaptic neurons.
The discovery identifies the earliest disease-causing change in brain function caused by presenilin defects and identifies potential new therapeutic targets for early-onset Alzheimer’s.
The work dovetails with parallel findings from Shen’s and other labs showing that defects in four Parkinson’s disease genes similarly stifle the release of the neurotransmitter dopamine. This confluence of data suggests that diminished neurotransmitter flow may be a precursor to neurodegeneration, a hallmark of diseases such as Alzheimer’s and Parkinson’s.
Shen studied the presenilin mutations in neurons in the seat of memory in the brain, the hippocampus, using conditional double-knockout mice. The genetic knockouts precisely targeted CA3 (presynaptic) and CA1 (postsynaptic) pyramidal neurons with mutations that impaired their production of presenilins. She found that the loss of presenilins in presynaptic neurons stifles the Ryanodine Receptor (RyR), which gates calcium release from the endoplasmic reticulum. This disruption knocks down calcium efflux from the endoplasmic reticulum, causing a shortfall that compromises the release of the neurotransmitter glutamate. This interruption of the signal from one neuron to the next impairs long-term potentiation, a key neural mechanism for forming and maintaining memories. Molecules in this cascade could represent novel therapeutic drug targets for inherited forms of Alzheimer’s disease, said Shen, who described these new insights in the July 30 Nature.
Students may contact Jie Shen at jshen@rics.bwh.harvard.edu for more information.
Conflict Disclosure: The authors declare no conflicts of interest.
Funding Sources: The National Institutes of Health; the content of the work is the responsibility solely of the authors.
