Alzheimer's disease Flashcards
1
Q
who first described alzheimer’s disease?
When?
A
First described in 1906 but Alois Alzheimers
2
Q
describe the discovery of alzheimers
A
Auguste De, a middle aged house wife was brought to Alois Alzheimer because she was struggling with her day to day activities
when she died, Alois observed her brain was more than a third shrunken than a typical person of that age
he drew two major structures that he saw - neuronal plaques adn tangles
3
Q
which region of the brain is primarily affected by alzheimers disease?
A
temporal lobe
4
Q
clinical symptoms are a reflection of…
A
a reflection of the circuitry that is effected in the brain
5
Q
when is a definitive diagnosis of alzheimers given?
A
when the patient dies and the plaques and tangles are seen in their brain
When the clinical symptoms appear as alzheimers then they are given the diagnosis of probable alzheimers
6
Q
what is dementia?
A
Impairment in cognitive faculties that interferes with you day to day activities
7
Q
what is unique about alzheimers disease in terms of tauopathies?
A
it has plaques and tangles
all dementias are tauopathies but other tauopathies dont have amyloid pathology and start in different regions of the brain
8
Q
what are the similarities and differences between different types of (tau) dementia?
A
similarites - all are tauopathies
differences - alzheimers involves amyloid pathology, different spatial pathology (starting in different brain regions)
9
Q
if the hippocampus-entorhinal cortex is effected what symptoms will be exhibited
A
impairment of recent memory
functions and attention
10
Q
if the cortex-basal nucleus of meynert is affected what symptoms will be exhibited?
(4) (basal forebrain)
A
failure of language skills
disorientation
impaired judgment
personality changes
11
Q
what do cholinesterase inhibitors do?
A
boost the circutry - so that the remaining neurons continues to be as functional as possible
basal nucleus of Meynert is a cholinergic system
Deficits in functions in the nucleus basalis of Meynert are observed in neurodegenerative diseases such as Parkinson’s disease and Alzheimer’s disease. Because of these changes, the cholinergic system was implicated in playing a role in the cognitive symptoms observed in Alzheimer’s disease
12
Q
what are neural plaques?
A
extracellular lesions made of amyloid Aβ
13
Q
what are neurofibrillary tangles?
A
– intracellular lesion, made of a microtubular protein tau (involved in transport)
14
Q
what is tau?
A
most abundant microtubular associated protein in the neurons
stabilises microtubules in neuronal axons
15
Q
give two reasons why we dont have effective alzheimers treatments
A
the neurodegeneration has progressed too far before the symptoms show up - too much dmaage has been done by the time there are clinical symptoms
there are no effective biomarkers - we cant pick up the presence of the abnormal protein before it starts to cause damage
16
Q
what percentage of alzheimers is familial?
A
15%
17
Q
give two things that are thought to reduce the risk of alheimers?
A
meditarranean diet - throught to be protective becase it has many antioxidants
excerise - it increase blood flow to the brain and reduces other comorbitities like cardiovascular disease and type 2 diabetes
18
Q
mutations in tau:
DO NOT cause….
but
DO cause….
A
DO NOT cause alzheimers
DO cause fronto-temporal dementia
19
Q
abnormal tau leads to formation of…
A
formation of tangles which causes neurodegeneration and clinical symptoms
20
Q
why was there debate in the cause of alzheimers and what settled it?
A
APP gene create amyloid precursor protein, several mutations were identified to lead to alzheimers disease, but there were non in the tau gene, it was thought to be a downstream effect
Mutations in in tau causse frontotemporal dementia (very similar to alzheimers, different region where the pathology starts), only have tau and still have degeneration
This made people change their mind, because tau was found to cause degeneration in other diseases but amyloid wasn’t – telling us abnormalities in tau are sufficient to cause degeneration
Amyloid is upstream of tau but it is when tau begins to become abnormal degeneration occurs
21
Q
when is Tau never mutated?
A
in alzheimers
22
Q
how is tau abnormal in alzheimers and other tauopathies?
A
tau is mutated
tau is hyperphosphorylated
tau is abnormally expressed
tau forms filaments
23
Q
what two tau abnormalities occurs in all tauopathies?
A
Tau is hyperphosphorylated and Tau forms filaments in all tauopathies
24
Q
when a disease is caused by an abnormal protein what two things lead to the clinical affects?
A
1) Loss of normal physiological function
2) Gain of toxic function
25
what percentage of tau protein in the body is phosphorylated?
in the adult body
5%
26
what percentage of tau protein in the body is phosphorylated?
in fetal development
20%
27
what percentage of tau protein in the body is phosphorylated?
in alzheimers
100%
28
how many phosphorylation sites are there on tau
75
29
how may tau be abnormally expressed?
normally 3 repeat tau and 4 repeat tau are expressed in an equal ratio
in alzheimers the ratio is wrong due to problems in regulatory eleements causing alternative splicing that results in excessive amounts of 3 repeat tau OR 4 repeat tau
the exons in the tau gene can be spliced differentially to include exons _ and/or _ and 10? the splicing occurs differently in disease causing abnormal expression of either 3 or 4 repeat forms
30
hwo many isoforms of tau are there
6
3 have 3 binding domains (3 repeat tau)
3 have 4 binding domains (4 repeat tau)
31
how was it discovered that tau in alzheimers was highly phosphorylated?
When isolated on a gel, tau has six different isoforms in normal, in alzheimers the bands are squished into three bands, retarded (heavier) gel motility, telling us that it is highly phosphorylated. – incubate with phosphatases the banding pattern reverted back to the control, or stain with phosphospecific antibodies.
32
why is formation of tau filaments damaging to a neuron?
it causes aggregation of protein that accumulates meaning that there is no space for the neurons to carry out its normal cellular function
33
what is different between the molecular tau in different tauopathies?
When tau misfolds and causes tangle – resulting in different types of conforma
Some taupothies look different than others, they are all aggregates of tau but the way tau is folded is different
Relationship unknown – potentially the phosphorylation pattern, or the ratio of 3 and 4 repeats
Pics disease have excessive amount of 3 repeat
PSP have excessive 4 repeats
Different conformas in diseases – do certain regions of the brain have different susceptibilities to different conformas
34
what is the normal physiological function of tau?
Inside axon there is a microtubular cytoskeleton
Microtubules are unstable, they breakdown all the time, tau is a stabilising protein that keeps them together
Tau important for enabling an efficient transport system to be created
35
what was the hypothesis set out by Sir lovestone?
whenever tau is abnormal, the first thing that happens is their ability to bind to microtubules fails, and the microtubule collapses, so no track for axonal transport to occur so that they can’t connect with other neurons
36
what evidence is there for sir lovestones theory
- there is a dramatic disruption of tau binding to microtubules when its phosphorylation - phosphatases reduces this effect.
- Microtubule cytoskeleton breaks down - when tau is highly phosphorylated you can see very few MT structures under electron microcope
- axonal transport disrupted - we see pile ups of vesicles in the axons
- this means neurotransmitter wont be released - we see that the neuromusclar junction is shrinking and dying confriming this
- Behavioural defects are seen (maggor races or righting assays)
- if you remove phosphoyrlatin this all returns to normal
## Footnote
- other proteins always wont reach the synapse so we see locomotor impairments or aparlsysi
37
what possible mechanisms are there for the toxic gain of function of tau?
expression of mutant or phospho-mimicking tau in animal models causes neurodegeneration
mechanism unclear but various suggestions including oxidative stress, apoptosis, necrosis or simple space occupying lesion
38
How can we counter abnormal tau mediated neuronal dysfunction?
(foundation -2)
1) reduce tau phosphorylation: kinase inhibitors
2) microtubule stabilising agents
39
what medication, used for a psychiatric disorder, was tried as a treatment for alzhiemers?
Lithium chloride: it was noticed that bipolar patients being treated with lithium chloride, had a much lower appearance of alzheimers disease thought to be due to the glycogen synthesis kinase activity of lithium chloride
40
why did the clinical trials of lithium chlorides (as an alzhiemers treatment) fail?
Thought to be a potential treatment for alzhiemers however when they reached clinical trials they did not work – there were too many side effects which caused reduced compliance (patients didn’t want to take it because they got too sick), meaning that they couldnt tell if the results were due to the drug or not.
These side effects were potentially due to glycogen synthesis involvement that is important for all neurons – not selective for neuronal kinase
41
give four peices of evidence that suggest NAP can rescue p-tau phenotypes?
* Even in the presence of highly phosphorylated tau, the axons look far more normal when NAP is applied
- It also reverted axonal transport – pile ups virtually disappear
- Neuromuscular junction also rescued
- When applying the drug to p-tau maggots it was able to almost revert their movement back to normal
42
what is NAP?
a neuroprotective drug candidate in clinical trials, stimulates microtubule assembly in the living cell
43
give an example of a microtubule stabilising drug
NAP
44
why did NAP fail in trials?
it worked on those with mild cognitive function however in patients with advanced alzhiemers it did not
Due to too much p-tau build up resulting in toxic gain of functions and formation of tangles. Also those that had the disease for years also had neuronal death which the drugs clearly can have no effect on
45
how could tau abnormalities cause neurodegeneration by toxic gain of function?
expression of mutant or phospho-mimicking tau in animal models causes neurodegeneration
mechanism unclear but various suggestions including oxidative stress, apoptosis, necrosis or simple space occupying lesion
and spread of pathology
46
to become aggregate prone means two things...
1) able to aggregate
2) able to convert normal protein to abnormal protein (like itself)
= prion like conversion/ template seeding
47
what are proteinopathies?
conditions where normal proteins have started to aggregate
misfolds -> becomes aggregate prone
48
why is it called template seeding?
Template seeding because a seed is able to create more of itself – the protein will have identical abnormalities to the seed its converted by
49
why is it knwon as prion-like conversion?
Named prion like conversion due to its similarity to the ability of prion to convert other prions in prion disease – infectious spread
50
describe the experiment that was the basis of Braak staging?
900 subjects ranging in age from 25-90 years were analysed
Disease spread reflect clinical symptoms
There is stereotypical spread of pathology across connected brain regions
It was observed that young people 20s-30s had tau pathology in the entorhinal cortex and over time 60s-70s this spreads out of the temporal cortex – and only then do the symptoms of Alzheimers appear
51
give an example backing up the theory that tau spreads
a women who died of Alzheimer who had had a tumour removed from her brain earlier in life, had a post mortem that showed tau pathology all over her brain apart from the area that had the tissue removed – getting rid of the circuit stopped the spread
If a circuit is disconnected it prevents the region getting the pathology
52
describe a simple experiment that shows that pathological tau spreads
Injection of brain homogenate from a 4RP3o1S mouse (disease tau (misfolds and aggregates)) into a transgenic mouse expressing human 4R tau (normal, doesn’t aggregate much) causes the spread of pathological tau from the diseased to the normal mouse
It stimulated the conversion of normal tau to pathological tau – we see aggregates appearing
53
give 3 methods of detecting Tau pathology
ThS and Gallyas silver, as well as immunohistochemistry using AT8 and HT7 antibodies (specific for Ser202/Thr205 phosphorylated tau)
54
give three principles of the spread of tau pathology
1. Aggregate prone tau can induce aggregation of non-aggregate prone tau.
A seed is required for the spread of tau pathology
2. propagation of distinct conformational strains
3. Tau aggregates exhibit prion-like transynaptic transmission
54
give three principles of the spread of tau pathology
1. Aggregate prone tau can induce aggregation of non-aggregate prone tau.
A seed is required for the spread of tau pathology
2. Tau aggregates act in a prion-like manner
propagation of distinct conformational strains
3. Tau aggregates exhibit prion-like transynaptic transmission
55
give three reasons why tau acts as a seed
requires tau
can be induced by tau filaments and oligomers
acts in a prion like template fashion
56
how could structural analysis of the specific structures of each tauopathies using cryo EM help us?
This could help up with therapies (understanding one it works in some patients or other), or as a biomarker for diagnosis, or help us understand why it affects a certain area
57
what are the similarities and differences between the different tau conformas?
58
what are the four components of a healhty brain?
neurons, synapses, glial cells, vascular system
59
how is alzheimers different from normal aging?
alzheimers is a different type of process that occurs much faster and leads to total independen loss of function
## Footnote
8 year survival from diagnosis to death
60
what type of memorr is lost in alzheimer's?
declarative memory
61
what is a common reason that patients with alzheimers die?
they die of pneumonia because they can no longer swallow
62
describe the three stages of alzhimers and the state of the brain at each
Preclinical Alzheimer’s – Up to 15 years of changes in the brain that go unnoticed, build of amyloid plaques
Mild cognitive impairment – onset of clinical AD takes a few years, some hippocampal volume already lost, 15-35% loss of synapses (moderately enlarged ventricles, cortical shrinkage, shrinkage of hippocampus)
Severe Alzheimer’s – much hippocampal volume lost, cortical thickness also lost (extreme shrinkage of hippocampus, extreme shrinkage of cerebral cortex, severely enlarged ventricles)
63
what stage of alzheimer's do we know most about and why?
We know much more about the later stages because we have studied the brains of those who have died
64
when bodys are donated after they have died of alzheimers, why are the studies no always helpful?
because they are collected 48hrs after death, losing much information in this time
65
what are the pathological hallmarks of AD?
| extracellular and intracellular
Extracellular:
- Amyloid plaques – Aβ
Also settle on blood vessel walls (cerebral amyloid angiopathy)
Intracellular:
- Neurofibrillary tangles – Tau
Also Inflammation plays a part
66
what is happening during MCI and early AD?
Amyloid beta deposition
(evidence suggests that Abeta deposition precedes the diagnosis of AD by about 15 years)
Loss of synapses in dentate gyrus and CA1
67
a team in kentucky asked the community to approve fast autopsys (4 hours) after death
what did this team discover about early AD and cognitive impairment?
The number of synapses in the dentate gyrus were extensively lost in early AD (44%)
this correlated highly with cognitive impairment
they also saw synaptic alterations in CA1 in mild cognitive alzheimers disease and milk cognitive impairment (55%)
## Footnote
the best correlate of cognitive impairment is the synapse loss (not plaque or tangles)
68
describe the events that occur in the hypothetical time course of AD?
1. amyloid beta accumulation
2. synaptic dysfunction
3. tau mediated neuronal injury
4. brain structure
5. cognition
6. clinical function
## Footnote
tau mediated neuronal injury could come before synaptic dysfunction
69
how is amyloid beta formed?
formed after sequential cleavage of the amyloid precursor protein (APP)
Aβ protein is generated by successive action of the β and γ secretases
The γ secretase, which produces the C-terminal end of the Aβ peptide, cleaves within the transmembrane region of APP and can generate a number of isoforms of 30-51 amino acid residues in length
70
what are presenilins?
Presenilins (PS1 and PS2 ) are part of the gamma secretase complex
(the first proteins where mutations were found, cause more cleavage at Abeta, found in familial alzheimers disease)
71
give examples of genes which when mutated result in a certainty that people will develop alzheimers disease
how do they do this
mutations in APP and PS1
result in an increase concentration of Abeta in the brain
72
what is bace1?
the major beta secretase for the generation of amyloid-β peptides in the neurons.
73
what percentage of alzheimers cases are sporadic and not familial?
95%
74
what was the basis ofthe initla hypotheisis which has driven Ad research (1992)?
that Abeta acted upstream of Tau
with an initial focus on plaques (now focus on soluble forms of Abeta)
75
how many mutations in the APP gene have shown to lead to early onset alzheimers?
more than 50
76
why is there a higher prevalence of alzheimers in those with down syndrome?
Down syndrom aka trisomy 21 is caused by a third copy of chromosome 21
amyloid precursor protein is found on chromosome 21
autopsy studies show that by ages 40, the brians of almost all individuals with Down syndrome have significant levels of plaques and tangles
77
describe the icelandic mutant
## Footnote
give the reason why
A mutation in APP that protects against Alzheimer's disease and age related cognitive decline
By studying the coding variants in APP whole genome sequence data from 1,795 icelanders, 1 in 100 had the APP mutation A637T
Older people (>80yrs) with the mutation appeared to be protected from cognitive decline
Carriers had much better cognition later in life than those who were non carriers
A673T reduces BACE1 cleavage of APP, resulting in lower Ab secretion
78
give three reasons that suggest that Amyloid beta is a causal factor in Alzheimer
* Mutations in APP and PS1 resulting in increased Ab production lead do early onset AD.
* Known association of Down Syndrome and AD (three copies of chromosome 21, where APP gene is located).
* Protective mutation of APP associated with reduced levels of Ab expression.
79
what are the risk factors for Alzheimers?
* Age.
* Lifestyle: diet, cardiovascular health, social factors
* Clinical: high blood pressure, diabetes, Down syndrome, depression.
* Genetic: Genetic variation: APOE variants: Modify AD risk.
Mutations: Amyloid precursor protein (APP, from which Ab is produced). Causes AD. Rare. Familial AD.
80
give examples of three genes that give a medium risk for alzheimers disease
TREM2
APOE4 (2 copies)
APOE4 (1 copy)
81
what genes are very common but give a low risk for alzheimers
MS4a
CR1
PICALM
BIN1
CLU
CD2AP
CD33
EPHA1
ABCA7
82
what is an MMSE score?
A test for cognitive impairment
Patients are asked a series of questions to determine the extent of their impairment
The maximum score for the MMSE is 30. A score of 25 or higher is classed as normal. If the score is below 24, the result is usually considered to be abnormal, indicating possible cognitive impairment. 0 would be the score if they couldnt answer anything
83
what was the outcome of the first alzheimers vaccine trial in 2001?
they used an active immunisation against Abeta called AN-1792 of those with moderate to advanced AD
this was successful in its goal of clearing the plaques however did not rescue cognition
the trial had to be stopped because the people developed brain inflammation (potentially due to attack of Abeta in blood vessels of brain)
removing plaques in advanced AD is not enough to rescue or reverse impaired cognition
83
what was the outcome of the first alzheimers vaccine trial in 2001?
they used an active immunisation against Abeta called AN-1792 of those with moderate to advanced AD
this was successful in its goal of clearing the plaques however did not rescue cognition
the trial had to be stopped because the people developed brain inflammation (potentially due to attack of Abeta in blood vessels of brain)
removing plaques in advanced AD is not enough to rescue or reverse impaired cognition
84
give an example of a new antibody stretegy that has shown promise for mild to moderate alzheimers
Aducanumab
In 2017 and spring 2018, 2- and 3-year data from the long-term open-label extension phase of the PRIME study were being reported at conferences as continuing to show dose-dependent amyloid removal by up to 70 centiloids, and also as slowing cognitive decline as per exploratory analysis. (Alzforum)
approvied by the FDA, however has marginal effects and still controversy to whether amyloid clearance protects patients from cognitive and functional decline
85
for amyloid beta trials to function they need to ...
Use other types of immunisation (eg. passive by injecting ready-made antibodies, rather than) and
Be targetted to individuals earlier in the disease process.
86
how can we study alzheimers?
Patient brains
Mouse models
In vitro (primary neurons, iPSCs, cell lines, brain slice)
brain imaging, pathology, memory cellular, mechanisms
transgenic expression (eg trangenic expression of mutant APP, other genetic modifications)
application of amyloid beta (synthetic, from AD brain, produced by cells)
87
what is wrong with using mice to study alzheimers?
mice are not humans and we cannot fully recapitualte full AD phenotypes that are useful for analysign interaction between Ad molecules
## Footnote
however they do anbale us to go deep into the cellular mechanisms, transgenic expression of mutant Abeta forms, apply synthetic abeta to see what happens more acutly and in vitro
88
describe the study that used Morris water maze to analyse how is expression of mutant APP caused cognitive impairment
Morris water maze.
Measures spatial memory.
Acquisition of memory: Mouse is trained for 10 days to find a platform (not visible).
Measure of memory: On a test trial the platform is removed and the number of crossings to where the platform was is counted, or % time spent in each quadrant.
If they have a mutation in the APP then they will not perform the same, on day 10 they will see the same results on day 1, no memory created
Mice expressing human APP with a familial AD-causing mutation (hAPP), and normal tau protein, fail to remember the location of a platform in the MWM.
## Footnote
Expression of APP with familial mutations (Sw,Ind) in mice leads to cognitive impairment
89
how was basal synaptic transmission in hippocampal slices assessed in mice?
90
the study that assessed basal synaptic transmission in hippocampal slices from mice discovered what?
Expression of APP with familial mutations in mice leads to synaptic loss
This seminal paper demonstrated that there can be a change in synaptic function before plaques appear in the brain of mice.
These results highlighted the role of Ab oligomers as opposed to plaques as causal agents of neuronal dysfunction
At mice 4 month old only has 60% capacity but no plaque
91
describe the experiment that showed that Abeta oligomers were repsonsible for dendiritc spine loss
Grew brain slices in organotypic culture (sterile) in control conditions neurons had beautiful spines
Addition of abeta monomers and the spines were fine
Add Abeta oligomers then the spines were lost
(much lower concentration used, a lower more similar to in human brain, then they cause the spines to go away)
92
what is long term potentiation?
a process involving persistent strengthening of synapses that leads to a long-lasting increase in signal transmission between neurons. It is an important process in the context of synaptic plasticity
93
what is required for Amyloid beta to inhibit synaptic plasticity?
Tau
94
describe the study that showed that Abeta dimers were responsible for cognitive/LTP impairment
take brains of those suffering from amyloid pathologies and extract Abeta to see what oligomers are present
In alzheimers there was strong presence of monomers and dimers
P-AD denotes a patient who had Abeta pathology but no cognitive impairment and no dimers were presnt in their sample
- we see more dimer present in those with cognitive impairment
secondly extracts from AD brains were injected in mice and the action potential was measured
the AD extract caused a lower synaptic potential ie LTP impairment (and synaptic dysfunction)
95
describe the experiment that shoewd that tau is required for Abeta to inhibit synaptic plasticity in hippocampal slices
application of a control and abeta extract to wild type and tau knockout mice
In the wt mice, the abeta extract showed a decreat in action potential
In the Tau knockout mice the abeta extract showed no difference from the control extract (ie didnt decrease the action potential or effect the synaptic plasticity)
**Amyloid beta did not see a decrease in LTP in tau knockout mice**
We need tau for abeta to impair synaptic plasticity
96
describe the experiment that uses a switchable transgene to study the chronic effects of amyloid beta in a mature brain
| what was discovered that could help in therapy
Switchable transgene (with doxycycline switch). Mice raised with a doxycycline diet to suppress the gene expression
When mouse develops normally, and then begins to accumulate Abeta (take away doxycycline), then test various things
At beginning of switch then 3 and 12 week after
after switch there is abeta accumulation
at the 3 week mark there is impaired synaptic plasticity and effects on short term memory
at 12 weeks plaques deposition has beguna dn there are effects on long term memory
at 3 weeks if you begin giving doxycycline again to stop APP expression then the LTP is noraml again (potential for Abeta targetting if addressed early at short term mem stage)
97
give three reasons to think that Abeta is a driver of AD
* Clear genetic link between Ab overproduction and AD.
* Similar pathological progression of early and late onset AD (LOAD).
* Ab impairs synaptic function in cell culture and mouse models.
98
Tau can have __ and __ function in alzheimers
permissive and detrimental
| normal function and gain of function
99
reducing endogenous tau ameliorates ____ in an alzheimers disease mouse model
Reducing endogenous Tau ameliorates Abeta-induced deficits in an Alzheimer’s disease mouse model
100
mutatnt APP enhances ____ in Tau mutant mice
Mutant APP enhances tangle formation in Tau mutant mice
101
wild type mice can learn to locate a hidden platform in the morris water maze
what happens to the memory of mice expressing human APP with a familial mutation (hAPP)?
have impaired memory
102
wild type mice can learn to locate a hidden platform in the morris water maze
what happens to the memory of mice with hAPP but with a genetic knock out of tau protein ?
## Footnote
human APP with a familial mutation (hAPP)
have normal memory
103
from mouse models, what interaction is suggested to cause lateral entorhinal cortex impairment in early AD?
Interaction of amyloid beta and tau
104
what are primary prevention methods for AD?
occuring pre MCI lifestyle changes can modify the tragectory of AD progression
105
what are secondary prevention methods to modify the trajectory of AD?
| (potential targets for therapies)
Occuring in the MCI years during cognitive decline - here is where the actual therapies will work
Limiting amyloid beta or tau accumulation
Addressing earliest neuronal dysfunction
106
how does Abeta cause excitotoxicity?
107
how does Abeta cause Tau re-distribution from axons to dendrites?
108
in vivo, what has been shown to trigger early synaptic dysfunction?
caspase3
signalling to calcineurin causing AMPAR endocytosis and spine loss
109
what causes loss of dendritic spines?
Synaptic removal of AMPA receptors in response to Ab
Abeta signal to calcineurin causing AMPAR endocytosis resulting in spine loss
110
what cause plasma membrane disruption?
| slide 78
Amyloid beta oligomers may form membrane pores and disrupt Ca2+ homeostasis.
Ca2+ dependent proteases such as calpain
111
what synaptic functions does Abeta affect?
112
how does Abeta cause defects in axonal transport?
113
dominant missense mutations in what two genes have been involved in early onset familial alzheimers disease (FAD)?
Presenilins and Amyloid precursor protein (APP)
114
breifly describe what the basal nucleus of meynert is
The basal nucleus of Meynert (NBM) subserves critically important functions in attention, arousal and cognition via its profound modulation of neocortical activity and is emerging as a key target in Alzheimer's and Parkinson's dementias
constellation of cholinergic neurons in the basal forebrain
115
breifly describe what the basal nucleus of meynert is
The basal nucleus of Meynert (NBM) subserves critically important functions in attention, arousal and cognition via its profound modulation of neocortical activity and is emerging as a key target in Alzheimer's and Parkinson's dementias
constellation of cholinergic neurons in the basal forebrain
116
what is braak staging?
Braak staging is a histopathological construct that allows for the differentiation of several disease phases based on the anatomical distribution of tau neurofibrillary tangles
117
what is the normal role of tau?
the role of normal tau in the body, currently it is involved in protecting genomic architecture, regulating myelination and synaptic plasticity, iron homeostasis and neurogenesis.
118
what is excitotoxicity?
a phenomenon that describes the toxic actions of excitatory neurotransmitters, primarily glutamate, where the exacerbated or prolonged activation of glutamate receptors starts a cascade of neurotoxicity that ultimately leads to the loss of neuronal function and cell death.
119
what are some causes of excitotoxicity>
The molecular mechanism that triggers excitotoxicity involves alterations in glutamate and calcium metabolism, dysfunction of glutamate transporters, and malfunction of glutamate receptors, particularly N-methyl-D-aspartic acid receptors (NMDAR). On the other hand, excitotoxicity can be regarded as a consequence of other cellular phenomena, such as mitochondrial dysfunction, physical neuronal damage, and oxidative stress.
120
how does excitotoxity cause cell death
his type of excitotoxicity can be divided into three steps. It starts with the induction, which begins with the overactivation of ionotropic glutamate receptors (iGluR), such as N-methyl-D-aspartic acid receptors (NMDAR), α-amino-3-hydroxy-5-methylisoxazole-4-propionate receptors (AMPAR) and kainate receptors (KAR). NMDAR display a high permeability to both sodium and calcium This ionic influx is followed by water influx, leading to cell swelling and mitochondrial dysfunction. The final step of induction is the activation of metabotropic glutamate receptors (mGluR), activating pathways regulated by diacylglycerol and inositol 1,4,5-triphosphate (Zivin and Choi, 1991). Amplification and expression are the following stages. These consist of exacerbated metabolic activity, further disruption of ion gradients, elevated electrical neuronal activity, and mitochondria dysfunction
121
how does gsk3beta function as a molecular link between abeta and tau?
GSK-3 has been proposed to function as a molecular link between Aβ and tau in AD pathogenesis [61]. Aβ activates GSK-3 [62,63], which in turns phosphorylates tau [64]. On the other hand, GSK-3 regulates amyloid precursor protein (APP) metabolism and Aβ production and promotes neuronal death induced by Aβ
## Footnote
* Inhibition of the tau kinase GSK3b, in wild type mice, prevents the inhibitory effect of amyloid beta on LTP.
122
what evidence is that abeta could be a target if addressed early on?
mice with APP transgenic mutations with indcucible doxicycline swicth, switch on for 3 weeks, abeta accumulates, if switch back on then LTP is back to normal
123
describe the evidence/ interactions that show abeta oligomers are pathogenic species
Diverse evidences support the notion that Aβ oligomers are the drivers of neurodegeneration which occurs in Alzheimer disease (147).
Some of the pathways involve the activation of glutamatergic metabotropic mGluR5 receptor (leads to CDK5 activation and tau phosphorylation)(148) and that of caspase-3 which leads to Akt1 cleavage (leads to GSK3beta phosphrylation and tau phsophorylation)(149).
Other interactions with Na+ , K+-ATPase activity include ERK2 downregulation as well as the N-methyl-Daspartate (NMDA) ionotropic glutamate receptor activation (150, 151), closely related to Na+ , K+-ATPase activity (Fig. 3).
In fact, results recorded in several experimental models suggest a close relationship between the activity of Na+ , K+- ATPase and NMDA receptor in intact cells (152-154). Aβ oligomers modify the activity of calcineurin (146), known to enhance Na+ , K+-ATPase activity by its dephosphorylation (15, 16). Besides, Ca2+ influx through the NMDA receptor activates calcineurin and protein phosphatase 1, thus modifying Na+ , K+-ATPase activity (155). Activation of calcineurin (by caspase 3 or otherwise) also causes AMPAR endocytosis and so spine loss
