Alzheimer’s Disease Pathophysiology Flashcards
basic
What is a monomer ?
a molecule such as an amino acid, sugar, fatty acid, or nucleotide
what is a dimer ?
two monomers joined together
what is an oligomer ?
a combination of monomers (amino acids) into a structure consisting of a few number of monomers
what is a polymer ?
a combination of monomers (amino acids) into a structure consisting of a large
number of monomers
what is a protein ?
a combination of several polymers
explain Alz pathology ?
What is confirmation of a protein ?
shape of a protein
explain conformational change
change in the shape of the protein … misfolded proteins
Explain Protein Aggregation
clumping or accumulation of mis-folded proteins
Summary
Monomer Combinations 1
Monomer Combinations 2
Monomer Combinations 3
Confirmational Change
Tau propogation
Alz Features
What is impact of tangles and plaques …1…?
tangles and plaques get in the way of normal neurotransmission.
What is impact of tangles and plaques … 2…?
And when they get in the way of normal neural transmission, neurons can’t activate each other.
What is impact of tangles and plaques … 3…?
And when neurons can’t activate each other, neurons start to atrophy if they’re not getting stimulation. So, over a period of time, the entire brain just starts to atrophy.
brain atrophy - note widening of the sulcus , volume shrinkage
what are models of Alz disease management ?
univariant and mulrivariant
explain univariant
So, a univariate model is, there’s one mechanism, one cause of Alzheimer’s disease. And if we can just treat that one cause then we should be able to reverse that. Medical model looking for the silver bullet
give examples of univariant
In the univariate model, in the world of pharmaceutical management and drug development, has had many different hypotheses and different mechanisms that have had clinical trials conducted for them. One was the amyloid hypothesis. One was tau propagation hypothesis, one was the neuro transfer hypothesis, I’ll go over some of these with you. And they were trying to find a single drug to impact Alzheimer’s disease. And just so you know, after the billions of dollars spent, they’ve never been able to identify a single drug to reverse Alzheimer’s disease or to even slow down Alzheimer’s disease.
and the multivariant model
And then you have the multivariate model, which is there’s a lot of variables involved. And there is a… these variables all have an influence on each other. And you can’t just treat it by one single mechanism, that you have to treat multiple mechanisms, really like a web. And this is where a personalized medicine approach comes in. So, let’s talk about the univariate model first.
more on univariant model
example of the univariate model, like when you look at the development of Alzheimer’s disease, the basic pathophysiology is there is the amyloid precursor protein, and there’s a pathway that’s normal.
And the amyloid precursor protein gets cleaved by an enzyme called alpha-secretase and the gamma-secretase.
And this then helps with normal neurological neuron functions. But in some states, the enzyme beta-secretases and the alpha-secretase comes in and this creates these protein aggregates, and amyloid plaques, and tau.
more on univariant
So, here you can see in this diagram several clinical trials that were published, where they were trying to either impact the amyloid plaque development by impacting these pathways with beta-secretase, gamma-secretase, or they’re trying to impact pathways that are involved with tau phosphorylation. And pretty much every single one of these clinical trials have failed, none of them worked. Despite billions of dollars being spent on these trials, when they tried to reduce the plaquing, they actually had some of these patients get dramatically worse.
take a look
