Alzheimers Flashcards
What is the biggest risk factor for alzheimers disease?
Age
What are other risk factors apart from age for AD?
- Family history
- Heredity
-Women more susceptible to Alzheimer’s
disease- Predisposing factors on X‐chromosome
- Estrogen protects against mitochondrial
toxicity in young women
- High blood pressure
- Smoking
- Obesity
- Low physical activity
- Low mental activity
- Severe head trauma
- unconsciousness and retrograde amnesia
What are the physical features in a brain affected by AD?
- Neuronal death and tissue loss
throughout the brain - Cortex shrivels, damaging
areas involved in memory,
thinking and planning - Shrinkage of hippocampus:
key role in forming new
memories - Ventricles (fluid-filled spaces)
grow larger - Nearly all brain functions
affected
What are the two lesions of alzheimers disease?
- Senile plaques of β‐amyloid (Aβ) (extracellular)
- Neurofibrillary tangles of phosphorylated tau,
a microtubule- associated protein (intracellular); found in dead and dying neurons
What are the earliest stages of Alzheimer’s in the brain?
- Plaques and tangles form in brain
areas affecting memory, learning,
thinking and planning - May appear 20 years before
diagnosis
What are the mild to moderate stages of alzheimers in the brain?
- More plaques and tangles form in
brain areas affecting memory,
learning, thinking and planning - Affects speaking and understanding
speech, spatial awareness - May experience confusion and
difficulty expressing thoughts and
feelings - Problems serious enough to affect
work or social life - Stage lasts 2 to 10 years
What are the advanced stages of alzheimers in the brain?
- Cortex severely damaged,
widespread neuronal death, brain
shrinks - Stage lasts 1 to 5 years
- Completely dependent on
caregivers - Loss of speech, apathy and
exhaustion - Cause of death usually external
(e.g. infection of pressure ulcers or
pneumonia)
What are the techniques used to diagnose alzheimers disease?
What are 3 main loci linked to familial AD? (mutations in these)
Amyloid precursor protein (APP)
Presenilin 1 (PSEN1)
Presenilin 2 (PSEN2)
Mutations in these can cause Alzhiemers
What are the genetic risk factors in AD?
- Apolipoprotein E (APOE)
-APOEε4 allele 3x risk in heterozygotes
and 15x in homozygotes
What is the amyloid precursor protein (APP)?
- Transmembrane protein
- Large extracellular domain and small intracellulr domain
- Gene has 19 exons
APP can be alternatively spliced into 3 variants : APP695, APP751 and APP770. Which of these is most abundant in the brain?
APP695
APP can be cleaved into different peptides by alpa, beta and gamma secretases. What are one of these peptides known as?
beta amyloid
amyloid precursor protein (APP) mutations can alter how the protein is cleaved. There is over 25 mutations found that can lead to incorrect beta amyloid. These mutations cause a change in beta amyloid length to
42 or 43 amino acids in length
- making it more hydrophobic and amyloidogenic (more likely to aggregate)
There are other proteins in the family of Amyloid precursor protein (APP). These are APLP1 and APLP2, why are these not involved in AD?
these proteins are not amyloidogenic (cannot form aggregates)
What is the function of APP?
Primary function of APP is not clear
May act as a growth factor:
- generation, differentiation and migration of neurons (within brain)
- Neurite (axon or a dendrite) outgrowth
- Regulation of synpatic function
Binds to molecules in the extracellular matrix like:
- heparin
- laminin
May be involved in cell-matrix adhesion and vesicle trafficking
What is presenilin-1?
Multi-pass transmembrane protein found in brain cells
Subunit of gamma-secretase complex: cleaves amyloid precursor protein (APP)
Presenilin-1 has 40 different possible mutations which leads to altered cleaves to APP. What is the pattern of inheritance involved when this protein is mutated? How does this alter the onset of AD?
Autosomal dominant
onset lowers to 28 years old