?-secretase and ?-secretase.
The two enzymes that are involved in amyloidogenic processing of APP.
Misfolding
A change in conformation of a protein. If this change results in the ?-sheet conformation, several proteins in this conformation can clump together.
They are hydrophobic, which makes sense because they are inserted into a membrane; ? helix
What is the biochemical nature of the amino acids that comprise the transmembrane domain of APP, and why does this make sense? What is the physiological secondary structure of these proteins?
The disordered amino acid region (1-10 aa) makes interactions with the membrane, causing water to enter the membrane. Then, upon ?-secretase cleavage of C99, the newly-formed A? peptide will leave the membrane and adopt the ?-sheet conformation after bein
What is the sequence of events that (1) leads to A? ejection from the membrane and (2) induces it to adopt the ?-sheet conformation?
Autosomal dominant
What Mendelian expression pattern of AD-related mutations?
True
(True or False) Animal models have demonstrated that APP mutations cause not only plaques but also cognitive deficits.
- Swedish Mutation (K670M/N671L)
- Dutch Mutation (E693Q)
- Arctic Mutation (E693G)
- London Mutation (V717I)
What are the APP/A? sequence mutations that we discussed in class?
Swedish Mutation (K670M/N671L)
A mutation of the APP sequence that is associated with familial forms of Alzheimer's disease. It is found right upstream of the A? sequence and increases the likelihood that BACE will cleave APP by 100X.
Dutch Mutation (E693Q)
A mutation of the APP sequence that is associated with familial forms of Alzheimer's disease. It induces cerebral amyloidosis.
Arctic Mutation (E693G)
A mutation of the APP sequence that is associated with familial forms of Alzheimer's disease. It enhances ?-amyloid protofibril formation by accelerating the ability of it to misfold and aggregate;
it doesn't directly alter A? production
n*.
London Mutation (V717I)
A mutation of the APP sequence that is associated with familial forms of Alzheimer's disease. It is located downstream of the usual ?-secretase cleavage site and enhances the ability of ?-secretase to cleave at the 42nd a.a. of A?.
Since APP is on chromosome 21, Down syndrome patients have a higher propensity to produce A? plaques since they have a higher concentration of APP.
How is Down syndrome related to Alzheimer's disease?
- It is extracellular
- It normally has a core composed of the ?-amyloid peptide
- It can be cored (with an intensely stained core with a weak periphery stained-halo) or diffused. Human AD has both, while animal models have only diffused (we don't know wh
What are some characteristics of the A? plaque?
Amyloid
A broad term for a protein that has the following characteristics:
- Insolubility in water
- ?-sheet conformation
- Largest aggregates deposit extracellularly
- Positive to staining with specific dyes, such as Congo Red (that can give a red color or light
A?40, A?42, and A?43; A?43, because it has the most hydrophobic amino acids, which are important for adoption of the ?-sheet conformation; A?42, because A?43 is produced in very small amounts
What are the three main types of A? peptides? Which is predicted to be the most toxic? Which is actually the most important for toxicity assessments?
1:5
What is the ratio of A?42:A?40 prior to conditions that promote A?42 production, as is seen in Alzheimer's disease?
When patients are grouped according to the CDR, (1) A?42 plaques have the highest level of immunopositive staining and (2) both diffuse and core A?42 plaques follow the progression of the disease, while A?40 does not.
What is the experimental evidence that A?42 plaque deposition follows the progression of Alzheimer's disease?
CDR
An assessment of dementia severity in Alzheimer's disease from 0-5. This measurement can allow for tracking of the progression of the disease.
In one publication, mice that were modified to produce a lot of APP were implanted with a camera to track plaque development. The researchers noticed that a plaque formed within 2 days and reached its peak staining intensity within 6 days.
What is the experimental evidence that A? plaques can form rapidly?
Within 2 weeks of tracking plaque development, developing neurites were noticeably more curved, suggesting that it takes only 2 weeks to produce an abnormality.
What is the experimental evidence that rapidly formed A? plaques have local toxicity?
Boutons that were adjacent to the developing plaque were more swollen, suggesting that the plaques can cause neuronal architectural changes that change neurite characteristics. However, it is hard to directly implicate the plaque and not the oligomers.
What is the evidence that A? plaques can induce presynpatic pathology in close proximity to plaques?
Oligomer
A group of 2-50 molecules that have hydrophobic interactions. Unlike plaques, they can be either soluble or deposited.
Cells were designed to express a form of APP that produced a lot of A? (7PA2, i.e., modified CHO cells) that was secreted into the extracellular environment (i.e., the cells' incubation medium) and compared to controls (CHO-). The A? content of this mediu
What is the experimental evidence that the three main types of soluble A? oligomeric species are monomers, dimers, and trimers?
Cells were designed to express a form of APP that produced a lot of A? (7PA2, i.e., modified CHO cells) that was secreted into the extracellular environment (i.e., the cells' incubation medium) and compared to controls (CHO-). The cells were removed from
What is the experimental evidence that soluble A? oligomeric species alter hippocampal EPSPs?