The role of astrocytes in Alzheimer's disease

Video transcript

• 0:10 – 0:32  It's an amazing time to be a glue biologist and particularly it's an amazing time to be studying astrocytes in the context of normal Physiology, that is the development and normal functioning of the brain, but also under pathological conditions like chronic neurogenic diseases, acute injuries, insults and infections and inflammation.
• 0:33 – 0:42 And the reason I think it's really exciting is we now have the tools available to start addressing some really exciting questions to which we don't know the answers to.
• 0:42 – 0:49 So what is a reactive astrocyte or for that matter, what is a reactive microglia or a reactive oligodendrocyte?
• 0:49 – 0:50 And we have a few ideas.
• 0:50 – 1:04 We know that there are some context dependent and initiating dependent reactive states of these cells, but looking more closely at the heterogeneity of these responses is going to be really important going forward.
• 1:04 – 1:17  Is the response of an astrocyte to Alzheimer's disease the same throughout all stages of the disease or does it change from prodromal stages to early Alzheimer's disease to late stage dementia?
• 1:17 – 1:25 And I think this will be very, very interesting from an academic sense, but also very, very important from a drug development stance as well.
• 1:25 – 1:35 Also really important and interesting because we have the capacity and the tools to this now is what are the mechanistic induces of these reactive subtypes.
• 1:35 – 1:52 We have some idea for scar forming reactive astrocytes, we have some idea for pro inflammatory neurotoxic reactive astrocytes, these being induced by STAT-3 mediated mechanisms and pro-inflammatory microglia in both instances.
• 1:52 – 1:57 But we don't have any indication for other reactive subtypes of these cells in the context of different diseases.
• 1:57 – 2:07 Astrocyte function, and particularly reactive astrocyte function in chronic neurodegenerative diseases like Alzheimer's disease, is a fascinating topic for investigation.
• 2:07 – 2:24 Historically, we would discuss astrocyte responses and microglial responses in diseases like Alzheimer's disease as being correlated with the disease and not really being indicative of the early induces of the disease or progresses of the disease.
• 2:24 – 2:44 But a lot of recent GEO (Gene Expression Omnibus) studies have really shown that mutations or at least snips that are aligned with mutations associated with these diseases are in genes that are highly expressed or solely expressed in both microglia and astrocytes, diseases like APOE, TREM-2, things like this.
• 2:44 – 2:56 And So what has been really interesting for us and for a number of people in the field is trying to determine now what functional changes these mutations would cause in these cells that highly express these genes.
• 2:56 – 3:04 And this has LED us to a number of conclusions that we are further investigating, and a number of other groups around the world are further investigating as well.
• 3:04 – 3:18 So the first is, do astrocytes in the context of Alzheimer's disease lose normal functions such as trophic support of neurons that could be indicative of how neurons are dying in Alzheimer's disease.
• 3:18 – 3:32 So if an astrocyte would normally provide traffic support to a neuron, if they stop providing that traffic support, would this be sufficient to initiate the death of neurons that is associated with Alzheimer's disease?
• 3:32 – 3:53 Similarly, if we know that astrocytes are really important in the release of synaptogenic molecules, that is, molecules that would help form connections or synapses between neurons, would a loss of that normal physiological function lead to a decrease in the synapse density that is seen very early in the disease progression?
• 3:53 – 4:07 Similarly, if we look at microglia, we know that microglia are extremely competently able to prune and remove synapses both during development and throughout normal life in both rodents and in humans.
• 4:07 – 4:18 And it's been shown by Beth Stevens and Soyon Hong and a number of others that the microglial pruning of synapses is increased very early in disease progression.
• 4:18 – 4:31 And so perhaps the loss of synapse density or loss of the numbers of synapses early in disease could also be due to an increase in the phagocytic capacity of these micro glare in diseases like Alzheimer's disease.
• 4:31 – 5:00 So I think together, not only do we have genetic implication from mutations from 10s of thousands of patients with AD and with a number of other chronic neurodegenerative diseases as well, But we also now have the cell biological and mechanistic understanding of how these mutations may be playing a role in changing the functions of these cells such that we can better understand how they may play a role in the initiation and the progression of these diseases.
• 5:00 – 5:15 Over the last few years, we've become increasingly interested in reactive astrocytes that are induced by inflammatory insults, which are actually very similar to astrocytes or an astrocyte subtype that is activated in chronic neurogenic disease.
• 5:15 – 5:24 And we found a close association between microglia, the resident immune cells of the brain and astrocytes in the initiation of this reactive response.
• 5:24 – 5:33 And what we found quite interesting, but obviously not surprising at all, as well as the fact that microglia respond first to these insults and injury.
• 5:33 – 5:47 And I say not surprising because the pathways involved for these responses that are largely mediated by Toll-like receptor 4 and MyD88 not or lowly expressed by astrocytes, but are highly expressed by microglia.
• 5:47 – 6:03 But microglia respond first to these insults and injuries and they release a plethora of cytokines and signaling molecules, of which three that are really important for the astrocyte reactive response include interleukin 1A, tumor necrosis factor alpha and the complement component C1Q.
• 6:03 – 6:20 So one of the things we've been taken by is the fact that although it's been known for many, many decades that in a whole wide range of chronic neurogenic diseases following acute traumas and injuries or infections, that there are changes in the astrocytic profile.
• 6:20 – 6:27 Very early on this was done by staining, looking for the cytoskeletal protein, glial fibrillary acidic protein or GFAP.
• 6:27 – 6:36 But more recently this has been done in a transcriptomic sense using microarrays, RNA sequencing and more recently single-cell sequencing.
• 6:36 – 6:52 And it has been alarming to us and very surprising that although the response has some subtleties within different diseases, there are some similar profiles of reactive astrocytes that are common across a wide range of neurodegenerative diseases.
• 6:52 – 7:18 So recently we discovered that a reactive astrocyte subtype that releases a neurotoxin that specifically targets both mature neurons and mature oligodendrocytes, but not in the other cells in the central nervous system is very common among diseases such as Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis and multiple sclerosis, but also very, very common in just normal aging as well.
• 7:18 – 7:25 More recently, we have described a subtype of reactive astrocytes that are induced by a new inflammatory mediators from microglia.
• 7:25 – 7:36 And these reactive astrocytes seem more common in acute inflammatory insults and chronic neurodegenerative diseases like Alzheimer's disease, Parkinson's disease, and multiple sclerosis.
• 7:36 – 7:42 And in this instance, these reactive astrocytes are taking on a negatively responsive phenotype in the brain.
• 7:42 – 7:53 That is, they disassemble synaptic connections between neurons and release a neurotoxin that is able to specifically kill mature neurons and mature oligodendrocytes in the CNS.
• 7:53 – 8:03 So in this instance, removal of these reactive astrocytes has a net positive outcome on the brain because the reactive astrocyte phenotype itself is having a negative influence on the CNS.
• 8:03 – 8:17 So we have found that when we are characterizing reactive astrocyte subtypes in postmortem human tissue sections, that this neurotoxic form of reactive astrocytes is only present in regions of neurodegeneration.
• 8:17 – 8:29 So for instance, in patients with Alzheimer's disease, we see these reactive astrocytes in the hippocampus, a region that degenerates in Alzheimer's disease, or in the prefrontal cortex in early stages of disease.
• 8:29 – 8:42 And similarly, if we were look in amyotrophic lateral sclerosis, patient donor tissue, we can see these reactive astrocytes in the motor cortex, the medulla and the spinal cord, but not if we look elsewhere in the brain.
• 8:42 – 8:46 And what's particularly interesting is if we look at normal aging.
• 8:46 – 8:50 This is work that was spearheaded by Laura Clark at Stanford University.
• 8:50 – 8:58 We can see that these reactive astrocytes are present in regions that are more susceptible to degenerations, such as the hippocampus in Australia.
• 8:58 – 9:17 So this lets us know that correlatively these astrocytes are present in regions where neurons are degenerating, but also that these astrocytes are not present in regions where neurons are not degenerating, which gives us strong evidence that they may be at least a correlative, if not a causative reason for the death of these neurons.
• 9:17 – 9:31 And one of the things that we're doing now is taking this one step further to try and determine within those regions of degeneration whether or not these reactive astrocytes are present before the neurons die or are only correlated with when the neurons are dying later in the disease.
• 9:31 – 9:38 And whether or not the reactive astrocyte phenotype is homogeneous or heterogeneous within those regions as well.
• 9:38 – 9:52 So we already know that not every astrocyte in a region of degeneration is activated down this pathway, but what we would like to know now is whether or not every astrocyte that is reactive is taken on the same phenotype.
• 9:52 – 10:07 But moving forward, one of the things that excites me is the advent or the ease of access to do single-cell transcriptomic analysis and single-cell ataxic to really look at subsets of these cells in the context of disease.
• 10:07 – 10:23 Are there particular reactive subsets of microglial astrocytes that are present very early in disease, or are there particular subsets that don't occur in patients that are not susceptible to developing such diseases as Alzheimer's disease and Parkinson's disease?
• 10:23 – 10:40 And this is going to provide a wealth of information not only about the transcriptomic changes in these cells, but it'll also give us amazing array of targets that we can use to produce antibodies to so that we can visualize these cells in tissue sections from patient donors.
• 10:40 – 10:49 But also it will provide us with the capacity to produce new mouse lines so that we can actually look at the functions of these cells and the changes in brain function.
• 10:49 – 11:05 If we remove these particular subsets, it's also going to be very interesting determining whether or not the functions or the changes in the function of these cells are having a net positive or net negative effect on the other central nervous system cells they're interacting with.
• 11:05 – 11:14 So one could imagine that removing an astrocyte that is secreting a neurotoxin would have a net positive effect on the brain.
• 11:14 – 11:28 But recent as evidence from Susan Krausman's lab in Austria has shown, in the context of prion infection, in which these neurotoxic reactive astrocytes are formed, the removal of these astrocytes actually has a net negative response in the brain.
• 11:28 – 11:39 Such as the prion infection is actually speed up and and infects more of the brain, which of course has an overall deleterious effect for CNS function.
• 11:39 – 11:46 So the time has come that we are learning a lot more about what these functions of these cells are and how that changed the disease.
• 11:46 – 11:51 But the context of what effects they may have is what I think is going to be really exciting going forward.
• 11:51 – 12:00 And we're only learning more about this every day with the advent of new technologies to visualize and sequence these really important cells of the central nervous system.