BCH 419 Alzheimer's Disease & ALS (exam 1)

Examples of familial AD mutations

(1) "Swedish" mutation increases B-secretase cutting at its site. --> this mutation increases the substrate binding affinity for B-secretase cleavage--> which leads to more AB. (2) mutations near the gamma-secretase sites make it prefer a site that yields 42 amino acid long peptide (AB 42) instead of 40 amino acid long (AB40) --> and with this the 42 AA peptide is much more aggregation prone than the AB 40 peptide. (3) some mutations are in presenilin (gamma-secretase) genes that cause the gamma-secretase to prefer cut site that gives AB 42. (Not a problem in the APP gene)

genetic risk for Alzheimers disease.

-APP mutations (trisomy 21) : three copies of the chromosome that contains the APP gene. ---> people with this mutation will have more APP, and thus they will make more AB -Also if there are mutations in gamma-secretase genes then this leads to more AB oligomers.

ALS symptoms

-weakness in hands, arms, and or legs -fasciculation or cramping in the arms or legs -thick speech or impairment of the use of arms or legs -in more advanced stages: we see shortness of breath or trouble breathing and difficulties swallowing.

________% of ALS cases are sporadic

95%

Amyotrophic Lateral Sclerosis (ALS):

ALS causes dysfunction/death of motor neurons leading to severe paralysis, with little or no effect on cognitive abilities -ALS involves motor neurons, but this is a different mechanism than Parkinson's. -there are no cognitive impairments as a result to ALS.

ALS Is also called

Lou Gehrig's Disease, he may not have had ALS though, they think it might have been a concussion.

non-amyloidogenic pathway

Normal processing of APP. we generally start with APP and it is acted on by alpha-secretase (it cutes APP in a certain spot). Next step, the gamma-secretase acts on what is left of APP to give p3 and AICD.

drugs for ALS

There are some helpful drugs for ALS patients, but they generally treat symptoms and not the cause. RNAi and stem cell approaches are being pursured. -RNAi reduces SOD1, (plausible) -stem cell research could be really hard

hallmark of Alzheimer's:

amyloid plaques and neurofibrillary tangles (1) neurofibillary tangles: fill up the entire cell, the cell is dead and not functioning. (2) amyloid plaques: occur outside the cells -> both are harmful to neurons.

amyloid plaques size:

can get very large

The neurofibrillary tangles are...

clumps of protein called tau. in a healthy nerve cell, the tau protein maintains the cells internal skeleton and aids in transportation within the cell. -But in some circumstances, tau can begin to clump abnormally and if it continues it will kill the cell. this clumping leads to Alzheimers tangle.

alzheimer's brain

if we compare an Alzheimers diseased brain and a healthy brain, we will see atrophy and obvious shrinkage in diseased brain -researchers are coming up with blood tests to identify if a patient has alzhimers or on the path to alzhiemers. As of now we can only definitively identify if a person had alz disease -right now they are taking serum samples from people and watching for 5-10-20 years and looking for markers that present in people who get alz.

ALS is RARE and usually exhibits _____________ onset

later onset. stephen hawking is an exception, he got ALS in his 20s but this is extremely rare. more common in males than females.

how to help stave off Alzheimers

maintain active social life keep fit healthy diet enjoy puzzles, brain activities, continue to learn

other than aggregation of hyperphosphorylated tau, what else happens when the tau protein becomes unbound and phosphorylated?

microtubules will be unstabilized when the tau proteins become unbound and phosphorylated. --so we lose microtubule integrity --and the build up of aggregates. (both harmful)_

The stages of Alzheimers and symptoms

mild: memory loss, language problems, mood and personality changes, diminished judgment. moderate: behavioral, personality changes, unable to learn or recall new information, long-term memory affected, wondering, agitation, aggression, confusion, require assistance with ADLs Severe: Unstable Gait, incontience (soil themselves), motor disturbances, bedridden, dysphagia

20% of familial cases are due to

mutations in superoxide dismutase (SOD1) that cause it to aggregate. this is the prominent genetic mutation. -chaperones and proteosomes are both good at preventing aggregation from occurring. people generally with aggregation diseases have a mutation with these two mechanisms (chaperones, and proteosomes)

Brain scans

now using non-invasive brain scans to observe brain activity. -these brain scans are done with positron emission topography (PET) shows how Alzheimers affects brain activity. The left image shows normal, right shows brain affected by Alzheimers. The blue and black areas in the right image indicate reduced brain activity resulting from the disease.

how do amyloid plaques form?

plaques contain ABeta protein produced by processing of amyloid precursor protein (APP) by the amyloidogenic pathway.

the ABeta (AB) produced by the amyloidogenic pathway is...

released outside the cell: and this is the reason that plaques form outside the cell. The ABs are prone to aggregate with one another and Beta-amyloid plaques form and grow larger. these are toxic to cells. Remember that these Beta-amyloid plaques that characterize Alzheimers disease contain ABeta (AB)

mechanisms involved in familial and sporadic ALS are...

similar. -in familial ALS mutant SOD1 exhibits oxidation at a number of residues, including cysteine 111, and oxidized SOD1 is prone to aggregation and is toxic. -Also they found that SOD1 in patents with sporadic ALS is also oxidized, and both mutant SOD1 and wild type SOD1 isolated from tissues of sporadic ALS patients are able to inhibit axonal transport function. -transgenic mice with reduced levels of SOD1 do not exhibit any major side effects so RNAi against SOD1 is being considered as a possible strategy for treating ALS ---> We can drop the levels of SOD1 way down, cannot fully get rid of it like lamin A in progeria patients, but you can reduce it a lot. -dominant negative diseases are good targets for RNAi treatments.

what are some approaches that are being pursues to prevent/ treat AD, that actually treat the causes?

some approaches that are targeting amyloid production/removal are: (1) to get something past the blood-brain barrier to inhibit the secretase. --> But this could have negative side effects because it stops the pathway of the game-secretase forming p3 (2) aggregation inhibitor: -> this would be useful for so many disease including Alzheimers. (3) removing the plaques: immunotherapy: the goal is to get the immune system into the brain to dissolve these plaques. proteasome that can clear the AB (if they can get in Brian)

in healthy person Tau

stabilizes microtubules (there is an equilibrium when tau is bound to microtubule) -BUT the PHOSPHORYLATION of Tau releases it from microtubules. But the released, phosphorylated form of Tau will form toxic aggregates. -Hyperphosphorylated Tau = very long, toxic aggregates. - these hyperphosphorylated taus lead first to reversible neuronal dysfunction, but over time will lead to permanent neurodegeneration and functional deficits. -SO inside dead neurons is the tau and hyperphosphoryalted tau

current drug treatments target...

symptoms rather than cause of Alzheimers. we treat symptoms. each of the treatments are impinging on brain chemistry --some treatments are patches, and some are pills

amyloidogenic pathway:

this is the Bad pathway. This pathways starts with APP, and instead of being acted on by alpha-secretase, it is acted on by Beta-secretase. Beta-secretase cuts APP slightly higher than normal, but this slight change is just enough to make a big difference. Next, the same gamma-secretase used in the non-amyloidogenic pathway to cut the Abeta (AB) off. and the product for this pathway results in AB instead of p3. -The product for this pathway, AB is aggregation prone... and so we will see the oligomerization of these that will become plaques. they start small, and continue to grow larger. -Beta-secretase is BAD.

what do plaques and tangles look like in the in brain sections?

you can see in the image that there are orange/yellow plaques present in the tissue. -> and you also can see neurons that are black.. its almost as if the tangles are like black toxic ink, squirted into the neuron.