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AD/PD 2022 | Alzheimer’s risk genes and their effect on synapses
Thomas Südhof, MD, Stanford University School of Medicine, Standford, CA, speaks on the loss of synapses, one of the earliest pathophysiologically relevant events in Alzheimer’s disease, correlating with cognitive decline. There are a large number of genes associated with an increased risk of Alzheimer’s disease, but the biology behind the associations is largely unknown. Prof. Südhof outlines his work using human neurons, derived from embryonic stem cells and induced pluripotent stem cells, to understand the effect of the genetic mutations observed in Alzheimer’s disease. Generating conditional mutations produced purely isogenic neurons, allowing more precise analysis of the effect of a given mutation on neuronal properties. The results show that the Alzheimer’s risk variants confer ability in neurons to increase synaptic formation. This finding suggests that gene mutations may not be detrimental to synaptic function directly. This interview took place at the AD/PD™ 2022 Conference in Barcelona, Spain.
Transcript (edited for clarity)
It is well-known that in Alzheimer’s disease, one of the earliest events that is pathophysiologically relevant is the loss of synapses and that correlates best with cognitive decline. It is also well-known that a large number of genes are associated with the risk of Alzheimer’s disease, and specifically variations in a large number of genes are associated with increased risk for Alzheimer’s disease...
It is well-known that in Alzheimer’s disease, one of the earliest events that is pathophysiologically relevant is the loss of synapses and that correlates best with cognitive decline. It is also well-known that a large number of genes are associated with the risk of Alzheimer’s disease, and specifically variations in a large number of genes are associated with increased risk for Alzheimer’s disease.
But the biology of these genes is largely unknown. The work that I described today, not today, the work that I described in my talk, was part of a larger set of studies that utilizes human neurons which we derive from stem cells, IPS cells and ES cells, to integrate the functions of the genes that are associated with Alzheimer’s disease and to understand better what happens when these genes are mutated, as is observed in some cases of Alzheimer’s disease.
The critical component of these studies that I discussed is that we are not just mutating these genes and clones that we then propagate and use to make neurons. Instead, we are generating mutations that are conditional and thereby are able to analyze neurons that are precisely isogenic. Because one of the problems in studying human neurons that are derived from IPS or ES cells is that if you study mutants, they’re rarely isogenic, truly isogenic, because they’re always derived by clonal propagation of mutated cell clones, which are no longer isogenic even though in the literature they are called isogenic.
This allows us to analyze precisely the effect of genetic variation on neuronal properties. It should be noted these are exclusively studies of neurons and not of astroglia, not of microglia, and by no means do these studies imply that astroglia or microglia do not have a major role. It does. It’s just that the studies focus on neurons because neurons are, after all, the cells that form the synapses that are impaired in Alzheimer’s disease and so that’s why we study them.
Our studies, in a nutshell, show that somewhat counterintuitively, variance, genetic variance, associated with the increased risk in Alzheimer’s disease in human neurons confer an increased ability to form synapses, not a decreased ability, a finding that has either perplexed my friends and colleagues, or made them feel slightly cautious. We can’t explain these results in the sense of the disease, but we also feel that it is a little bit naive to think that these gene changes would necessarily be detrimental to synaptic function itself. Because, after all, Alzheimer’s disease is a disease that develops over decades, not something that is apparent in childhood, as you would expect for any genetic change that impair synaptic function directly.
Prof. Südhof serves on the board of directors for Sanofi SA and for CytoDel Inc., and is a consultant for Alector, Boost, Recognify, Simcere, REATA, Catalio, Danaher, Elysium, Jupiter, and NeuraLight. Most of these companies have drug programs directly or distantly related to Alzheimer’s or Parkinson’s disease.