Alzheimers Disease Flashcards
What tissue changes occur during Alzheimer’s disease?
Atrophy of the brain - most apparent in the temporal lobe
Post mortem examination of the brain shows wide sulci, displaying the atrophy that has occurred
Frontal lobe is usually sparingly affected and the occipital lobe remains unaffected
Amyloid plaques formed extracellularly
Flame shaped intracellular fibrils called neurofibrillary tangles
What are amyloid plaques and how are they produced?
Amyloid plaques are made of deposits of short insoluble fragments of ß-amyloid..
ß-amyloid is formed from a larger protein called amyloid precursor protein (APP), which is a transmembrane protein thought to be a cell surface receptor, have a role in the development of synaptic connections and the learning associated with neuronal remodelling process.
The normal APP processing involves cleavage to form soluble fragments thought to have neuroprotective properties. In AD the first cleavage is altered, resulting in the formation of ßA, which has a strong tendency to aggregate.
The aggregates accumulate outside of nerve cells producing oligomers, which then form immature fibrils and then mature fibrils which form the plaque.
What effects do ß amyloid have on the brain?
Research shows deposits of ßA are coincident with haem deposits, usually indicative of microhaemorrhage; however it is undetermined whether microhaemorrhages are caused by the plaques, or the plaques by the haemorrhages.
ßA oligomers and prefibrils have sown to catalyse the production of ROS causing oxidate stress, and are more effective than mature fibrils in initiating apoptosis. Mature fibrils however; are more effective in stimulating the expression of ß-secreatse
Consensus is that all forms of Aß are potentially neurotoxic, however most seems to be mediated by ROS, and involves bound or co-deposited iron or aluminium.
What are neurofibrillary tangles?
These structures are made exclusively from an abnormal form of tau protein, which is along intracellular protein that holds together microtubules. As microtubules are dynamic structures, the tau protein needs to have the ability to detach and reattach.
The AD, the tau detaches from the cytoskeleton and undergoes phosphoyrlation, which prevents its reattachment. This leads to hyperpolarisation of tau in the cell and the decay of microtubules.
Hyperpolarised tau has the tendency to form paired helical filaments with itself, becoming insoluble. As the microtubules disintegrate, the paired helical filaments accumulate within the cell and form the classical tangles within the main cell body. When this occurs within the axons and dendrites, it forms neuropil threads.
The disintegration of the cytoskeleton and accumulation of the amorphous material leads to cell death. The tangles are very though, so remain in the tissue for a long time.
What are the risk factors for developing Alzheimer’s Disease?
Age
Gender - Women have a higher risk post menopause
Diabetes, hypertension and atherosclerosis
Repetitive head injury
Deficiencies in B vitamins
Genetics
What genetic factors predispose a person to Alzheimer’s disease?
No clear genetic cause has been identified, however the fact it seems to accumulate in families points to an inheritance pattern.
Variants of the apolipoprotein E gene (ApoE4) has shown to be associated with atherosclerosis and AD. Having the gene does not determine if the person develops AD or not, but if they have the gene, they develop the disease earlier, develop factor and have more plaques and tangles.
Trisomy 21 (Downs syndrome) have an increased with of AD. This may be due to the fact that the gene for APP is found on chromosome 21, and variations of the gene have shown to have a link to AD.
Mutations in presenelins have also shown links to AD.
