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.