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BIOL 6397 CELLULAR NEUROSCIENCE Mon-Wed 4-5.30 PM - Cell Neuro Lecture 21 Alzheimers Disease
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00:02 This is 22 of Neuroscience, Cellular . And the last uh lecture,
00:10 discussed migraines and type of physiology of . So we talked about this cortical
00:16 depression instead of cellular mechanism and underlying spread of the migraines and also generating
00:24 no susceptive perception is actually of pain the trigeminal ganglia and trigeminal uh nucleus
00:34 . So in this article which is on your supporting election materials, I'd
00:41 for you to take away filth. I'd like for you to take away
00:46 phases of migraine, which we mentioned time, but we didn't call it
00:51 one, phase two, phase phase four. And this has been
00:54 technically better divided and better described. phase one is described, defined as
01:06 , the interplay between alterations and stasis the onset of climb. The interesting
01:16 is that people think that this pre space is just a aura phase,
01:22 it is not, it is actually that precedes aura. So in this
01:30 , also you have the explanation again the nooter men nooter and how they
01:40 activated with increased para and pathetic And we also talked about how microglia
01:46 activate them by releasing the cytokines and clima molecules. But the second stage
01:53 the second phase of migrating is So in principle, this phase premonitory
02:01 and stated here in the paper can as early as three days before the
02:09 of of migraine or or on the of migraine headache. It's unlikely that
02:16 last for so long or may last it is maybe to an hour or
02:24 that is then followed by a And some patients, I guess they
02:31 feel that something is changing in this phase. You have a little bit
02:38 fatigue, there's a mood change, little bit of sadness, uh muscle
02:46 , sensitivity, photophobia to light. And it's all pointing to the involvement
02:58 these structures that we've already talked about brain stem limbic system in certain cortical
03:04 during the early stages of this So this is this is something that
03:10 proceed days before. It's almost as things are slowly changing in your
03:16 maybe you feel it and it's not same as art. Now, these
03:22 is the aura and it is not the case that those that experience migraine
03:30 horror, but one third of migraine are preceded by aura and there is
03:37 international classification of headaches disorders, literature societies and needs and try to define
03:47 migraine is, define what aura Uh migraine with aura as recurrent attacks
03:55 minutes, more unilateral, fully reversible sensory or other C N symptoms that
04:02 develop gradually and are usually followed by headache and associated migraine symptoms. The
04:09 prevalent is visual disturbances. And uh as in my case,
04:17 personally, during aura, you start patches of your visual field. So
04:24 don't see things the same way. it's not like it's hallucinations. So
04:29 just actually losing or misperceiving certain And there is a lot of
04:37 If you recall when we talked about system and the primary visual cortical
04:43 we talked about the orientation problems right V one. And people actually report
04:52 of these very interesting geometrical lashes that almost part of pro possibly of cortical
05:01 . And this geometry could be very likened, potentially the geometry of the
05:07 activation or arrangement, orientation columns. this um activities in the cortex.
05:14 not because uh uh it could coincide the spatial appearance of them and the
05:23 that we have in the cortex, common symptoms, truth, sensory speech
05:29 , motor disturbances as well as disruption higher cortical functions. OK. So
05:36 is the, the the, the correlate CS D. And we discussed
05:43 coral spreading depression. The third phase a headache, throbbing, pain of
05:52 . And we talked about geno vascular . And it's an adamant physio physiology
05:58 are involved in the distribution of pain people perceive in the migraine and we
06:06 about some major events. Remember we two hypothesis, the ul of potassium
06:12 CID glutamate hypothesis for the generation of coral spreading depression and also for the
06:21 . No, this is the, is the article that, that you
06:32 attached. So you can review and a little bit more if you want
06:37 about the premonitory or and headache And uh I would say that what
06:47 after the headache is that there is depression in the cortical activity or also
06:54 physiological homeostatic activity in the whole And that's why I was explaining that
06:59 is not just the pain in the . Typically the following day, a
07:02 feels effects throughout the body or throughout muscle. So it does have seems
07:08 be what uh is like a systemic metabolic changes, stomach throughout the whole
07:18 due the, during this premonitory phase obviously after the headache attacks after the
07:25 attacks. Ok. Now, let's about Alzheimer's disease is another neurological uh
07:38 disorder is a dementia that is in elderly. And what is found?
07:48 example of this graph here is that have the incidence of ratio uh of
08:03 in individuals with Alzheimer's disease has elevated 87 fold at this age. So
08:13 this U shaped curve, it's a disorder. Remember we talked about how
08:21 most prevalent occurrence or incident of epilepsy diagnosis of epilepsies during the early ages
08:28 early development. And these are typically epilepsies. And then we talked about
08:36 U shaped curve and how with the of 50 there's an increase in the
08:42 of seizures and epilepsy. And these typically acquired forms of epilepsy,
08:48 traumatic brain injuries, cancers, a of unknowns, right to discuss
08:54 So on the right is Alzheimer's disease it shows that the incidence ratio of
09:03 in individuals diagnosed with ad with Alzheimer's . So if you have Alzheimer's disease
09:11 this age, you 50 and 58 is fairly early, you're 87 times
09:20 likely to have a bulls. So , epilepsy is a comorbidity to Alzheimer's
09:33 . Remember we talked about comorbidities, is something that is gonna help kill
09:39 faster seizure incidence drops at this age to, to, to 69.
09:51 still at the very older age is plus the people that have Alzheimer's is
09:59 , three times more likely to have . So there is a correlation,
10:05 is some sort of a correlation between disease and dementia and epilepsy. And
10:13 a very uh significant topic that's been in the last 5 to 10
10:19 Yes. So has there been like your knowledge like people that have maybe
10:24 like started having seizures as like an symptoms? Like, oh, I
10:33 , yeah, it's a it it's good question. So can you have
10:36 mild form of Alzheimer's. You really know what's going on with you.
10:39 then you would see like a seizure a, or, and people would
10:45 what's going on with you and they find Alzheimer's, it's just because of
10:49 . You could then, you yeah, but you would then
10:53 you know, which one started Maybe you had epileptic mutation or predisposed
11:00 seizures and epilepsy and you have inflammation that gives us the formation of plaques
11:06 Alzheimer's disease like that. So you're certain what started first or what started
11:11 . But there's definitely this correlation between , epilepsy and Alzheimer's disease.
11:20 so Alzheimer's disease, when we talk neuro modulators, remember we talked about
11:27 system and the ce codeine is produced Ponto memento complex here in ponds Ponto
11:41 in this basal nucleus of Manard right . And from here, Acey Coline
11:48 distributed into brain stem, the subcortical and into the cortical areas as
11:55 And this is the system. This the neuromodulator immune system that gets compromised
12:02 Alzheimer's disease. So these neurons that acetylcholine, they die and the neuro
12:11 . So there isn't that much of production of a loco. OK.
12:16 , a code system here is the system or the particular neuromodulator system in
12:24 brain that is in the ball that Alzheimer's pathology. The hallmarks of Alzheimer's
12:37 are Amyloid, blacks and neurofibrillary the tangles this is a normal brain
12:46 normal neurons, the neurofibrillary tangles will inside neurons inside the cells as they
12:54 . And tanggula, they start impeding transport, cellular transport, as well
13:01 delivery of goods to different parts of cell. Essentially starting to cramp their
13:08 and slowly kill them. The beta plaques are congregations of abnormally folded protium
13:17 gets aggregated into these clumps and these start growing bigger and bigger, getting
13:25 , getting surrounded by glial cells and start exerting a effect on the physiology
13:32 anatomy of neurons from the outside, the extracellular spaces, not only
13:38 obviously, uh plaques that are located will also start affecting glial functions because
13:45 between neurons, you have wheel functions glia will also be affected as involved
13:52 there's a lot of inflammation in Alzheimer's . A lot of times people will
13:57 about epilepsy or Alzheimer's brain. So brain is in flames, meaning that
14:03 a lot of inflammation in flame uh inflammatory molecules, a lot of
14:09 is unregulated. Yeah, basically If you look at the gross anatomical
14:18 , uh changes here on Alzheimer's disease severe Alzheimer's stages, you have really
14:25 moral meric changes, they have shrinkage gray matter. You can still see
14:31 lot of white matter, a lot connectivity, but a lot of cells
14:34 neuro degenerative, a lot of cells it's pretty severe and an overall shrinkage
14:41 the brain pattern um and loss of . So the artist re rendering this
14:48 from the National Institute of Aging, those plaques are interspersed among neurons and
14:56 essentially misfolded proteins that disrupt the activity communication between brain cells and kill brain
15:05 . It's a nice in your There are genetic, uh There's a
15:12 component of Alzheimer's disease. Um Late Alzheimer's disease at 67. Later,
15:21 evolve variant of a lipoprotein E A E gene, which is on chromosome
15:29 . OK. And if you have specific variant of that A O E
15:34 , you have an increased risk of Alzheimer's disease. It's involved in lipid
15:44 in the brain and A P O comes in several different forms or
15:50 each person inherits two A O all one from each biological patient
15:58 So that means that if you have certain variant of A O E or
16:06 like that, that gets passed to from the parent or from both parent
16:13 makes you susceptible to potentially developing Alzheimer's . So you can do 23 me
16:24 any one of these chromosomal uh genetic tests for ancestry and you can also
16:32 on uh diseases. So you can an next another 2030 40 bucks and
16:37 will say what genes you may have that could potentially predispose you. Uh
16:45 if it agrees that you have it your family, it's more likelihood you
16:50 be predisposed or inherent uh the genome develop that disorder. Uh Early onset
16:58 disease is typically associated with a P amyloid recursive protium, which is uh
17:06 chromosome 21 1 P S M one P S M two on two different
17:17 . Each one of the mutations that occur on the A P P
17:21 and uh uh a protein whose precise is still not very well understood
17:30 except that it gets cleaved the wrong in Alzheimer's brains. And because it
17:34 cleaved the wrong way from the it aggregates extracellularly and aggregates into amyloid
17:43 . Uh So this is because of A P P period. So abnormal
17:50 of this amy recursive protium, it's cell location and causes the aggregation and
18:00 of these amyloid plaster is a molecular basically. Um Behind the wax.
18:14 . Wow. Wow. Maybe this a good extra credit question here.
18:25 walk through this. We're smart. understand a lot of things that so
18:30 don't even need to read the You can read the legend can answer
18:34 lot of questions. Even when the credit sign, you figure paragraphs with
18:45 light goes right. So let's Number one A B A beta is
18:51 primarily by neurons in the brain. interacts within the lipid is a treated
19:01 micro and astrocytes in an isom specific . So, we have this amyloid
19:10 and it can interact with A E promotes the olym and aggregation of A
19:20 amyloid beta. So these guys A E and it is released and regulated
19:32 micro Glee. And aside, here shown right lipid A O E.
19:37 that guy when there is abnormal A production of cleavage goes, hey,
19:43 found you let's aggregate into a plaque before and the subsequent deposition of these
19:55 . Now, the interesting thing is do not form everywhere and they typically
20:03 some cortical regions in the hippocampus and lot of times in temporal lobes.
20:08 guess what happens, they migrate through . OK. So, and you
20:17 imagine if th those calcified aggregates migrating space are causing major disruption due to
20:24 neuronal activity. Connectivity of signaling inside have a deposit of these self
20:31 low density L D D R L L R A prone sulfate receptor media
20:38 of A beta by astrocytes and the . In addition to promoting the production
20:46 of A beta apo E four a beta clearance by reducing cellular uptake
20:51 transported more off the blood barrier is number five. First of all,
20:59 an outtake of this and there is disruption of blood one bar A O
21:06 two E two, overexpression enhances the of a data blocked by some insulin
21:16 mechanism. OK. That's number six here. So you have enzymes prote
21:24 enzymes that are degrading this. The proteolysis of neuronal A O E four
21:34 da da, da, da da neurotoxic fragments. That's number seven.
21:42 eight, we have neuro degeneration, synaptic accumulation and neuro degeneration and synapse
21:53 is number eight. Number nine. always, you have neuro inflammation and
21:59 degeneration. So again, this is process that is not neuronal process.
22:05 a process that is glial neuronal Certain elements come from glia, certain
22:11 get glee off neurons, they get . They have a way to uh
22:18 uh deposit the aggregates of blacks and plaque. As you can see,
22:22 start ruining, essentially breaking down in , affecting neuronal axons early on causing
22:31 pruning or illumination of the synopsis inflammation neuro degeneration of these neurons.
22:38 do you have to remember all of details? No, not all of
22:44 99 steps, but I may give as an extra credit to label these
22:49 steps, maybe. So that will you remember them. But in
22:54 I think important to know A O amyloid beta, which one comes from
22:58 one comes from neuron aggregation. And fact of this path of pathology that
23:05 aggregation of these causes. So I lucky enough that uh I was sitting
23:13 my office one day and I called Doctor Matthew Rasmin from Baylor College of
23:21 . And uh I said Matthew, you studying neal axons? And if
23:29 was looking at traumatic brain injury of traumatic brain injury affects the neuronal
23:36 He says, yes, I I said, you know what I'm
23:39 Alzheimer's, I was recording in from brains and mice and the inca
23:45 the hippocampus. I said, I'm that. And I said, I
23:50 if uh in the Alzheimer's model, would also find a disruption of axonal
23:58 and external function, we could find traumatic brain injury. He says,
24:03 idea, let's work on it. I thought I also have an interesting
24:07 that there's this not the, I even run the paper basically circles,
24:17 where, you know, exact uh , it's the same distance. And
24:24 would be used if you were reconstructing cell anatomy, let's say, and
24:29 wanted to measure the length of each , right? So you could
24:35 oh, it looks like this Ndri , you know, uh 15 micrometers
24:41 something like that. So I you know, what wouldn't it be
24:46 to use this method and plays this at the very center here and use
24:59 as the very center and then measure close yeah Amyloid beta plaque is and
25:11 effect it would have uh on the if it's located this distance away.
25:18 for example, this distance away, hypothesis was the closer the plaque is
25:24 the axon, the worse the axon and the worst axon will function so
25:29 we can apply this method for measuring distance, measure the distance from the
25:33 and then assess the damage to the . That was great. And we
25:38 for a while and we met a of times and then it very a
25:44 student, Miguel Maren and another uh , Jona Jankowski from uh Baylor College
25:53 Medicine. He got involved in the and a lot of really cool stains
26:00 the stain dili in uh this is P P. It's a double mutation
26:09 these animals and I'll be happy to this article if you want to.
26:14 at 11 months you see these dogs out here, the those are the
26:20 . OK? So this stain is to black. So you can see
26:23 it's six months in this transgenic animal that has a mutation and A P
26:30 and uh P T A genes, , produces blacks and la. And
26:39 a stain A was a can use stains from microglia to see the microglia
26:51 accumulating around the area where there is plaque, for example, with flavors
26:59 that's good for the amyloid plaques that amlo plaques. Yeah, that's the
27:04 that reveals am and then there is stain that you can reveal, you
27:10 these little branches coming off the these are axons and you can see
27:16 in between these cells and axons, are these plaques. So now we
27:24 the black in the center right here we stain so we can stain so
27:35 of neurons and then there is another that's specific for axons. So now
27:43 can see anywhere here, you can a white dash. This is an
27:49 , right? So you can tell close this axon is to the
27:57 And you can measure the length of the axons in normal brains and the
28:07 of all of the axons. So will have an average length of axons
28:12 some tissue, normal brains of 11 old mouse. And then you will
28:17 the plaques and 11 month transgenic And you will measure the length of
28:23 of the axons. So you can the average length. So you will
28:28 that oh on average in Alzheimer's my are shorter. But our question was
28:33 the ones that closer to the to to the plaques are affected to a
28:38 degree. And again, there's quite bit of data here. It shows
28:46 six month ball tissue, 11 month tissue staining for axons with this B
28:52 B spectrum, which is a specific for axons. So and then measuring
29:04 let's look at this, OK. I S length is this axon initial
29:13 length, what is axon initial segment for reducing the action potential? So
29:21 specialized area here, right, which NAV one point two and 1.6 and
29:31 DS here stacks on initial segment. . This is where the action potential
29:37 generated. And so we can measure length of the axon initial segment from
29:45 SOMA to the first myelin segment. that's how we act on the nickel
29:54 . And what we see is that six months, although there's already a
29:59 here, you're already starting to see . Although this is called the plaque
30:05 . How heavy is the burden the burden. So the more severe the
30:09 , the more plaques and more widely , the heavier is the burden of
30:14 plaques. So here there's already plaque but it's low burden. Uh And
30:22 is happening is you have Axion initial length. This is a double mutant
30:30 B P TT A, this is single mutant TT A one G mutated
30:36 this is N T G which which is non transgenic. So wild
30:40 animal. And seemingly there is no in the axon initial segments,
30:47 All of these bars are about the size. There's no significant difference.
30:52 when you look at 11 months and we look specifically at the both the
30:58 with the uh with the double the black column A B B and
31:04 A, you have a reduction from wild ban of all which is about
31:14 micrometers. I can't remember the exact now on top of my head,
31:17 18 micrometer lines for a an initial and it drops to about 12 my
31:26 either like. So you have shrunk space from 18 to about 12,
31:39 , 66. It's one about one , shorter initial segment. Well,
31:51 know, it's a pity that in study, we didn't address functionality and
31:58 at the firing properties of the action that study in separately when published.
32:06 it's a really cool study on how neurons are failing. And the closer
32:12 the plaques, they are, the they're failing to produce action controls.
32:16 we showed this together with a pharmacology here, uh Jason Nason a number
32:23 years ago. So this study is morphological study, right? A lot
32:29 stains transgenic animals. But there's no question is what does it mean to
32:35 function if you lose 30% of the initial segment? Does that mean you
32:41 less of action potentials? Or maybe don't produce any action or maybe you
32:47 two and you fail to produce You have now changed the action potential
32:53 dynamics significantly. And so the closer are, the closer you are uh
33:00 located, um the worse you are and in your ability to produce action
33:12 , uh the worse you're up in case of the length of that an
33:16 cycle, right? This is the slide. Actually, I said life
33:22 shorter. Your typical Alzheimer's disease treatments inhibitors since we hear commercials on
33:36 Are you taking you're taking? So have to check with your doctor if
33:41 can take some other medication. Uh a seal coline size and these cooner
33:50 . So we just looked at, get released by synoptic acetyl colon combined
33:57 IPIC in the C MS and metro colon receptors. And there's not the
34:05 that gets broken down by a colon the co and acetic acid colon gets
34:14 back preoptic. And with Colin, seal transfers for chat with the little
34:23 and becomes a little Cole, it's into bicycles and the cycle can
34:30 So what these scents do or they block A by blocking A is
34:39 prolonging the bi availability of the. , there is a problem here because
34:46 you kill all of the COVID producing , this drug is not affected if
34:52 no more Cyco released in the C S, if these nuclei, if
34:57 tone is completely down on the C S. And so what these drugs
35:03 both the ones that target an MD receptor and the ones that target cole
35:08 , they best slow down the progression the disease. There is no cure
35:13 Alzheimer's and there are not that many . This is not the same diagram
35:19 we saw for epilepsy, right? we saw for epilepsy, 1st,
35:24 and 3rd generation drugs, look at of these 10 different brand names,
35:28 voltage gated sodium channels. 10 different names targeting Gaba then prey. That's
35:33 cool release, presynaptic voltage gated calcium , synoptic many, many different targets
35:41 Alzheimer's, it's mostly inhibitors and there Melaine which is an antagonist for an
35:50 receptor. It's an interesting antagonist. only blocks open an NBA receptor.
35:58 why would that happen? Because once receptor opens it close position and has
36:02 certain confirmational shape. If it that means its confirmational configuration and shape
36:09 changed. Therefore, there might be new crevice or opening between amino acid
36:15 here in three dimensions that can now a new molecule binding to such as
36:22 . So why would you do And why would you target an MD
36:26 receptor block antagonize MD? A sheer cyto toxicity number one. And then
36:43 A receptor is there's too much You're having seizures. Remember you're a
36:48 possibility there's inflammation, what happens in and gliosis? He is releasing a
36:53 of glutamate and calcium. It becomes big burden. Now, you can
37:00 this N MD A receptor potential. . So you are preventing glutamate inside
37:08 by blocking an MD A receptor. think about this for a minute.
37:14 are some of the symptomologies of Alzheimer's ? We haven't discussed that, discuss
37:20 cellular mechanisms, the pathology. What the symptomology, impaired memory,
37:25 memory, impaired, safe spatial time orientation and then everything else.
37:32 , the early stages will be panic of not knowing where you
37:36 what time it is not recognizing or , people's names and faces. And
37:42 later stages is your brain is forgetting body and the vital body functions because
37:47 plaque burden can imagine now that it all over the cortex, affecting cognitive
37:53 , affecting your ability, your motor , ability for you to take care
37:58 yourself to the point where then the can swallow, can feed yourself,
38:05 know, taste anything and is up over the brain stem. It can
38:11 affecting vital brains, stone nuclei and you the heart rate. The uh
38:20 of these uh aspects that can be said novelty first. Yeah. Or
38:28 do we know that the year after create memories. It's involved.
38:39 it's a coincidence that their memories. incredibly important for elasticity, plasticity snap
38:49 very much mediated by an MD A something because it has a lot of
38:53 conductors and also is a strong influence calcium and activation of the intracellular cascade
39:00 now streamed. So what what I'm in the plasticity that we studied the
39:09 mechanism of plasticity and frequency code. rate code versus the spike code,
39:17 M B A receptor was necessary in to create that plastic, therefore necessary
39:23 order to create those memories or erase . Because if you consider L T
39:31 or potentiation, creating something new strengthening synapsis, then you can interpret L
39:38 D long term depression, which weakens and essentially eliminates them over time.
39:46 a process of forgetting. So both important brain space is finite. We
39:54 of remember everything that we encounter in lives and forgetting is a protective mechanism
39:59 us too. So, not so , right? Because if these patients
40:07 memories and these memories, unless some of plasticity in their aging brains,
40:13 amount of brains still activates an MD receptor. Now, the drug is
40:18 to active an MD A receptor. is I think that this is a
40:24 opportunity. There are other drugs that being developed. These are not the
40:28 two targets, but these are the targets, nicotine and acetyl coon
40:35 Somebody should say, wait a second . Why are you trying just to
40:40 uh uh degradation? Why can't you these acetylcholine receptors? The nicotinic one
40:48 is an atropic or the muscarinic one smoking cigarettes and nicotine is good for
40:56 brains. There is research that suggests activation of specific nicotine ace subtypes could
41:03 beneficial in Alzheimer's disease but it's So once again, this is a
41:12 that it has a huge pharma industry with it. Billions and billions of
41:21 that are spent by patients and sins some by um and it's just to
41:30 down the progression. So I always uh an undergraduate course And in this
41:38 , also is like think about different . You know, there's this is
41:41 is the way that we can start really smart, thinking about different
41:46 thinking outside the box of inhibitors, outside the box of a seal
41:53 maybe we need to target some of mechanisms that we just discussed here.
41:59 not prevent liquidated A O E instead the mechanism, find a molecule that
42:06 target specifically lipid apo somehow grab onto . And this all flag busting
42:17 This is a big topic and we something even checked and it goes to
42:22 plaque boo like explodes the plaque into pieces of micro, eats it all
42:27 and clean it all up. How about early detection of Alzheimer's disease
42:37 blood work E E G S F S are now becoming and,
42:44 and pretty prevalent and actually trying to what's going on at the early stages
42:49 Alzheimer's disease. And right now, and scientists are working on the algorithms
42:56 A I artificial intelligence and how to the brains based on the blood markers
43:03 other markers, the genetic markers and imaging information that they acquired how to
43:09 all of it to potentially predict if person is actually maybe even in the
43:14 stages of Alzheimer's, they may not it themselves yet. They just say
43:18 just speak very forgetful this year. . OK. So that ends our
43:25 and you guys are gonna be responsible formulating and discovering new drug for Alzheimer's
43:34 . No
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