Amyloid Beta Flashcards

1
Q

What are the components that make up a healthy brain?

A
  • Neurons
  • Synapses
  • Glial cells
  • Vascular system
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2
Q

What are the changes that occur across a life time for an aging brain to clinically diagnosed AD?

A
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3
Q

How is declarative memory effected in those with AD?

What part of the brain is thought to be effected alongside this?

A

Some have mild cognitive impairment which can progress to severe Alzheimer’s with a loss of daily living functions such as missing appointments, remembering names etc.

Declarative memory is a type of long-term memory that involved conscious recollection of particular facts and events

Doesn’t seem to affect procedural memory

effect on declarative memory suggests that something is going on in the hippocampus

may see that the hippocampus has shrunk in those with AD

Enlarged ventricles and shrinkage of cerebral cortex also in those with severe AD

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4
Q

Compare a healthy and Alzheimer’s brain

A
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5
Q

What are the pathological hallmarks of Alzheimers diseases?

Those with are extracellular and intracellular?

A

Pathological hallmarks of Alzheimer’s diseases

Extracellular (Abeta)

  • Amyloid plaques accumulate in the Blood vessels walls (this is known as cerebral amyloid angiopathy)
  • Black?

Intracellular

  • Neurofibrillary tangles (Tau)

Inflammation – activate glia

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6
Q

What is happening during MCI and early AD?

A

Blue dots are when imaging is done to look at the specific compound binding to plaques

Consistent 15 year gap

PiB is a radioactive analog of Thioflavin T, which is used in PET scams to image plaques in neuronal tissue

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7
Q

Tell me the anatomy of a neuron what are each of the components and their role

A
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8
Q

Tell me about synapse loss in patients with AD, what does it correlate with?

A

Extensive synapse loss in early AD

Highly correlated with cognitive impairment

Synapse loss in early AD 55% CA1, Scheff et al 2007

In early AD about half of the synapses are gone. Still have some capacity to learn and remember but not to the extent as those with NCI

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9
Q

What is the hypothetical time-course of AD events?

A
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10
Q

Amyloid beta and interaction with Tau- LO

A
  • Define what Ab is and discuss the evidence that links Ab with Alzheimer’s disease.
  • Describe amyloid beta trials.
  • Discuss experimental analyses in AD mouse models.
  • Discuss the experimental evidence which shows that Ab and tau interact in AD models.
  • Identify potential molecular pathways that link Ab and tau.
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11
Q

Tell me about amyloid proteins

A

There are many types of amyloid proteins and Amyloid beta is one of them.

They are

Misfolded

Aggregated

Insoluble

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12
Q

With Amyloid beta, are all the proteins insoluble?

A

No, there is a soluble form (Abeta oligomers) which are what is what is thought to be causing AD

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13
Q

Tell me about APP metabolism by the secretase enzyme

A

Cuts the plasma membrane which produces Abeta fragments alongside others

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14
Q

Mutations found in what have resulted in increased concentration of Abeta in the brain and are thought to be genetic components of AD?

A

APP and PS1

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15
Q

How many known mutations are there in the APP gene which lead to early onset Alzheimer’s?

A

>50

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16
Q

What have autopsy studies suggested a link between?

Why is this the case?

A

Autopsy studies have shown that by age 40, the brains of almost all individuals with Down syndrome (trisomy 21) have significant levels of plaques and tangles

APP (amyloid precursor protein) is in chromosome 21 and those with Down syndrome have trisomy 21

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17
Q

Tell me about a study on the mutation in APP which provides protection against AD age-related cognitive decline

A

Search for low-frequency variants of APP (risk modifiers for AD)

Studied coding variants in APP whole-genome sequence data from 1,795 Icelanders.

1 in 100 had the APP mutation A637T.

Older people (> 80 years) with the mutation appeared to be protected from cognitive decline.

Those with mutation were doing better than those without the A637T mutation

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18
Q

Tell me some evidence that suggests the strong genetic link of Abeta as a causal factor in AD?

A

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.

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19
Q

However…

A

>95% cases of AD do not have a clear genetic cause.

Understanding the causal links between Ab and neuronal dysfunction and neurodegeneration (e.g. using transgenic mice with APP and familial mutations) is needed

–> but sporadic Alzheimer’s may be caused by many other elements that we must understand before a therapy can be found (metabolism? Inflammation? Tau?)

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20
Q

What are the Alzheimer’s disease risk factors (for the non-genetic forms of the diseases- roughly 95%)

A

Age.

Lifestyle:

  • diet
  • cardiovascular health
  • social factors

Clinical:

  • high blood pressure
  • diabetes
  • Down syndrome
  • depression.
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21
Q

What are the alzheimer’s diseases risk factors (for the genetic forms of the disease- roughly 5%)

A

Genetic:

  • Genetic variation: APOE variants: Modify AD risk.

Mutations:

  • Amyloid precursor protein (APP, from which Ab is produced). Causes AD. Rare. Familial AD.
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22
Q

What is the extensive preclinical trajectory in AD?

A
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23
Q

What are some therapeutics for AD?

What are they used to treat?

Whats some issues with some?

A

AN-1792

  • Moderate to advanced AD
  • Had to be stopped
  • Led to Brain inflammation
  • Researchers at Southampton analysed PM brains

Aducanumab

  • Mild to moderate AD
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24
Q

Extensive preclinical trajectory in AD

A
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25
Q

Amyloid related therapeutics

A
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26
Q

Tell me about Amyloid beta trials , what they were carried out using and what they need to function

A

Ab appears to be a major target for Alzheimer’s disease.

Trials were carried out using active immunisation (stimulating the patient immune system) but were stopped because of serious side effects.

To function, amyloid beta trials may need to:

–> Use other types of immunisations (e.g., passive by injecting ready-made antibodies, rather than) and

–> Be targeted to individuals earlier in the disease process.

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27
Q

What are the studies for AD that you can do on patient brains?

A

Ethically can do Brain imaging, pathology and Memory

Brain imaging doesn’t tell that much

Could do EEG recordings and get ideas on plasticity and function of brain

28
Q

Why are mouse models used for AD?

A

Although they do not recapitulate full AD phenotypes, they are useful for analyzing interactions between AD molecules.

If Tau is present it tends to be found in those with AD as it is severe that it tends to be found in those in frontal temporal dementia and therefore shows in dementia before it would in AD

29
Q

Tell me how Alzheimers disease is modelled using patients and mouse models?

A
30
Q

Interesting review discussing that current research using Abeta oligomer needs better standardisation

The toxic Abeta oligomer and Alzheimer’s disease: an emperor in need of clothes

A
31
Q

A mouse model has showed that mice expressing mutant APP develop what with age?

What model can be used for this?

A

Mice expressing mutant APP develop with age

Comparisons of mouse and human brains and accumulation with plaques

Line 102 mice: animals can develop normally and then can remove doxycycline from diet and then they start expressing amyloid beta 2 days after that which can then be studied

32
Q

Tell me about a trial done on APP mice using the Morrise water maze

A

Measures spatial memory.

Mice is swimming but it doesn’t like swimming so looks for firm ground

In final trial the platform is removed

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.
33
Q

A study on the expression of APP with familial mutants (Sw, Ind) has lead to what?

A

Expression of APP with familial mutations (Sw,lnd) in mice leads to cognitive impairment

Memory retention in the Morris Water Maze

34
Q

Assessing basal synaptic transmission in hippocampal slices from mice

A

Plasticity study

35
Q

The expression of APP with familial mutations in mice has led to what?

What does this study suggest?

A

Synaptic loss

36
Q

Do the neuronal and synaptic defects occur before or after the plaques accumulate?

A

Before

37
Q

Abeta is toxic to neurons and synapses. It is dose dependent so what can happen within hours to days of this compound being present?

A

Causes death of neurons

Neurons without Tau proteins (Tau -/-) did not die

  • Therefore, require Tau to cause neuron death

Causes loss of dendritic spines

  • Amyloid beta oligomers cause this

Impair synaptic plasticity

38
Q

How does ABeta oligomers affect neurons?

A

Abeta oligomers decrease dendritic spin density in hippocampal pyramidal neurons

39
Q

Impairment of synaptic plasticity with amyloid beta

A
40
Q

What is done to look at the cellular and molecular aspects of learning and memory?

A
41
Q

What do both Alzheimer’s and Down syndrome brains contain?

A

Abeta Dimers (D)

42
Q

What do Abeta protein dimers do?

A

Abeta protein dimers isolated directly from Alzheimer’s brains impair synaptic plasticity (and memory)

43
Q

What is required for Abeta to inhibit synaptic plasticity in hippocampal synapses?

Tell me about this?

A

Tau is required

Normal hippocampal neurons in mice can undergo an increase in synaptic efficacy following high frequency stimulation (long term potentiation -LTP)

Amyloid beta reduces LTP of hippocampal circuits (interferes with synaptic plasticity) in wild type mice.

However, in mice that have a genetic knock out of Tau protein, amyloid beta does not interfere with synaptic plasticity.

Inhibition of the tau kinase GKK3b, in wild type mice, prevents the inhibitory effect of amyloid beta on LTP.

–> GSK3b is a link between amyloid beta and tau with downstream effects on LTP and potentially learning and memory.

44
Q

Studying chronic effects of amyloid beta in the mature brain

A
45
Q

The emergence of synaptic and cognitive impairment in an inducible APP model

A
46
Q

Is the early impairment of synaptic plasticity in vivo reversible?

A

Yes

47
Q

What role does Abeta play in Alzheimer’s disease?

A

Abeta as 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.
48
Q

Will targeting Abeta cure AD?

A
  • Assumption that studying Ab will shed light on LOAD.
  • Clinical trials targeted to reduce Ab have failed so far (intervention too late?).
  • It is clear that Ab is not the only clinical driver of AD (i.e., Tau, Inflammation).
49
Q

Our understanding of amyloid beta and tau is just beginning. Experimental evidence suggests that a therapy will have to address both pathologies to be effective.

A
50
Q

What does reducing endogenous Tau Ameliorate Abeta induce?

A

Deficits in an AD mouse model

51
Q

Mutant APP enhances tangle formation in Tau mutant mice

A
52
Q

What does the evidence from AD patients and mouse models show about the lateral entorhinal cortex?

A

That it is impaired in early AD

53
Q

Extensive pre-clinical trajectory in AD

A
54
Q

Modifying the trajectory of AD

A
55
Q

How does Abeta affect neuronal function?

Abeta affects neurons and synapses via multiple molecular mechanisms

Complex downstream cascades are engaged by Ab oligomers. Leading to impairment of synaptic plasticity, excitotoxicity, and dendritic spine loss

A
56
Q

Tau reduction prevents Abeta- induced defects in axonal transport

A
57
Q

Abeta causes defects in axonal transport

A
58
Q

Abeta mediated synapse loss

A
59
Q

How is the plasma membrane distrupted?

A
60
Q

What does the synaptic removal of AMPA receptors in response to Abeta produce?

A

Loss of dendritic spines

61
Q

What does Caspase-3 trigger?

A

Early synaptic dysfunction in vivo

62
Q

Abeta causes tau protein re-distribution from axons to dendrites

A
63
Q

ABeta causes excitotoxicity

A
64
Q

What are some challenges ahead with AD?

A

Alzheimer’s disease drug targets

Mechanisms that are normally used by neurons

AD therapies should re-establish the balance

65
Q

How is amyloid beta used as a diagnostic tool?

A

Positron emission tomography (PET) with PiB, and

Ab proteins in cerebrospinal fluid (CSF) in relation to pTau

66
Q

Think about

A
  • Is an amyloid-based therapy a potential cure for Alzheimer’s disease? At which stage of AD progression could such a therapy be administered.
  • What are the potential mechanisms of synapse loss in AD?
  • What is the link between synapse loss and memory loss in Alzheimer’s disease?
  • How can we translate all the knowledge we have generated in mice to develop actual therapies for AD?