Amyloid Beta Flashcards
What are the components that make up a healthy brain?
- Neurons
- Synapses
- Glial cells
- Vascular system
What are the changes that occur across a life time for an aging brain to clinically diagnosed AD?
How is declarative memory effected in those with AD?
What part of the brain is thought to be effected alongside this?
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
Compare a healthy and Alzheimer’s brain
What are the pathological hallmarks of Alzheimers diseases?
Those with are extracellular and intracellular?
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
What is happening during MCI and early AD?
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
Tell me the anatomy of a neuron what are each of the components and their role
Tell me about synapse loss in patients with AD, what does it correlate with?
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
What is the hypothetical time-course of AD events?
Amyloid beta and interaction with Tau- LO
- 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.
Tell me about amyloid proteins
There are many types of amyloid proteins and Amyloid beta is one of them.
They are
Misfolded
Aggregated
Insoluble
With Amyloid beta, are all the proteins insoluble?
No, there is a soluble form (Abeta oligomers) which are what is what is thought to be causing AD
Tell me about APP metabolism by the secretase enzyme
Cuts the plasma membrane which produces Abeta fragments alongside others
Mutations found in what have resulted in increased concentration of Abeta in the brain and are thought to be genetic components of AD?
APP and PS1
How many known mutations are there in the APP gene which lead to early onset Alzheimer’s?
>50
What have autopsy studies suggested a link between?
Why is this the case?
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
Tell me about a study on the mutation in APP which provides protection against AD age-related cognitive decline
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
Tell me some evidence that suggests the strong genetic link of Abeta as a causal factor in AD?
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.
However…
>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?)
What are the Alzheimer’s disease risk factors (for the non-genetic forms of the diseases- roughly 95%)
Age.
Lifestyle:
- diet
- cardiovascular health
- social factors
Clinical:
- high blood pressure
- diabetes
- Down syndrome
- depression.
What are the alzheimer’s diseases risk factors (for the genetic forms of the disease- roughly 5%)
Genetic:
- Genetic variation: APOE variants: Modify AD risk.
Mutations:
- Amyloid precursor protein (APP, from which Ab is produced). Causes AD. Rare. Familial AD.
What is the extensive preclinical trajectory in AD?
What are some therapeutics for AD?
What are they used to treat?
Whats some issues with some?
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
Extensive preclinical trajectory in AD
Amyloid related therapeutics
Tell me about Amyloid beta trials , what they were carried out using and what they need to function
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.
What are the studies for AD that you can do on patient brains?
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
Why are mouse models used for AD?
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
Tell me how Alzheimers disease is modelled using patients and mouse models?
A mouse model has showed that mice expressing mutant APP develop what with age?
What model can be used for this?
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
A study on the expression of APP with familial mutants (Sw, Ind) has lead to what?
Expression of APP with familial mutations (Sw,lnd) in mice leads to cognitive impairment
Memory retention in the Morris Water Maze
Assessing basal synaptic transmission in hippocampal slices from mice
Plasticity study
The expression of APP with familial mutations in mice has led to what?
What does this study suggest?
Synaptic loss
Do the neuronal and synaptic defects occur before or after the plaques accumulate?
Before
Abeta is toxic to neurons and synapses. It is dose dependent so what can happen within hours to days of this compound being present?
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
How does ABeta oligomers affect neurons?
Abeta oligomers decrease dendritic spin density in hippocampal pyramidal neurons
Impairment of synaptic plasticity with amyloid beta
What is done to look at the cellular and molecular aspects of learning and memory?
What do both Alzheimer’s and Down syndrome brains contain?
Abeta Dimers (D)
What do Abeta protein dimers do?
Abeta protein dimers isolated directly from Alzheimer’s brains impair synaptic plasticity (and memory)
What is required for Abeta to inhibit synaptic plasticity in hippocampal synapses?
Tell me about this?
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.
Studying chronic effects of amyloid beta in the mature brain
The emergence of synaptic and cognitive impairment in an inducible APP model
Is the early impairment of synaptic plasticity in vivo reversible?
Yes
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.
What does reducing endogenous Tau Ameliorate Abeta induce?
Deficits in an AD mouse model
Mutant APP enhances tangle formation in Tau mutant mice
What does the evidence from AD patients and mouse models show about the lateral entorhinal cortex?
That it is impaired in early AD
Extensive pre-clinical trajectory in AD
Modifying the trajectory of AD
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
Tau reduction prevents Abeta- induced defects in axonal transport
Abeta causes defects in axonal transport
Abeta mediated synapse loss
How is the plasma membrane distrupted?
What does the synaptic removal of AMPA receptors in response to Abeta produce?
Loss of dendritic spines
What does Caspase-3 trigger?
Early synaptic dysfunction in vivo
Abeta causes tau protein re-distribution from axons to dendrites
ABeta causes excitotoxicity
What are some challenges ahead with AD?
Alzheimer’s disease drug targets
Mechanisms that are normally used by neurons
AD therapies should re-establish the balance
How is amyloid beta used as a diagnostic tool?
Positron emission tomography (PET) with PiB, and
Ab proteins in cerebrospinal fluid (CSF) in relation to pTau
