Lecture 11: Alzheimer's Disease Flashcards
What is Alzheimer’s disease?
- a chronic degenerative brain disorder related to aging. Minor forgetfulness –> major memory disruptions –> generalized dementia –> widespread physiological dysfunction –> death
- First described in 1906 by Alois Alzheimer, a German physician
- Thought to cause 60% - 70% of all dementia worldwide
How do you diagnose AD?
- The only* true diagnosis of AD is post-mortem so it’s a bit difficult to get actual numbers of patients
- getting into the brain and looking at Neurofibrillary plaques and tangles (these are the only two things that separates Alzheimer’s from all other dementias) but this post-mortem diagnosis rarely happens because there is no point in confirming what we already know, and because the patient is already dead so there would be no benefit.
- Tentative diagnosis of AD is based on characteristic clinical features
What is the epidemiology pf AD?
- Most AD patients die of unrelated complications (e.g. heart attack, cancer, etc.) so numbers may be suppressed.
- Today, there are over 500,000 Canadians with AD and an additional 25,000 cases diagnosed every year.
- By 2031, it is expected that 937,000 Canadians will be living with AD (66% increase).
What are the clinical symptoms of AD?
Early symptoms:
– Short-term memory loss;
– Subtle problems with executive function;
– Apathy*; no emotion (present in early stages and stays consistent throughout the stages)
– Often disregarded as “Old Timer’s” disease.
Later stages:
– Difficulty with language;
– Disorientation; confusion (ex. who they are) which can generate the mood swings
– Mood swings;
Advanced:
– Loss of motivation;
– Loss of bodily functions;
– Dependent on caregivers.
What are hallmarks of AD?
- extracellular amyloid plaques and intracellular neurofibrillary tangles in cerebral cortex are stereotypical hallmarks of the disease
- Loss of cholinergic cells in the basal forebrain;
- Mass shrinking of cortical thickness can be observed in late stages of the disease.
- As disease progresses, AD patients experience degeneration of dendritic trees/branches, and general atrophy of neurons.
- These physical changes are associated with worsening of symptoms
in order to call something alzheimers disease, you have to look at what is causing the loss of neurons in those speicific brain regions. This is because the many different types of dementia affect these same parts of the brain so under a brain scan, the brain will look the same
What are the risk factors associated with AD?
- Genetic predisposition (~70% of risk);
- Exposure to environmental elements (e.g. aluminum);
- Immune reactions;
- Slow viruses;
- Prions (abnormal, infectious forms of proteins).
What is Acetylcholine?
- ACh is widely distributed throughout the brain, and plays a crucial role in both sympathetic and parasympathetic branches of the autonomic nervous system, as well as the CNS.
- ACh is responsible for muscle contractions, as its released at neuromuscular junctions.
- —> Botulin Toxin (botox), for example, inhibits ACh release
- —>nicotine binds to nicotinic ACh receptors acting like an agonist
Where are cholinergic cell bodies located?
- Basal forebrain: projects to the hippocampus & cortex
- Midbrain: project to the basal ganglia, thalamus, diencephalon, pons, cerebellum, cranial nerve nuclei and reticular formation
How is acetylcholine transmission related to AD?
- hippocampus and cortex both needed for cognitive function. Acetylcholine released from the basal forebrain and projected to the hippocampus and cortex is responsible for turning those areas on so you get the cognitive function (this is why nicotine and other drugs that increase activity of ACh enhance memory and helps with cognitive function)
- Cells in the basal forebrain are among the first to die in AD.
- –> Specifically in the entorhinal cortex; ento meaning inside and rhinal meaning nose but it has nothing to with olfaction or nose (smell). This is one of the major inputs to the hippocampus (so it is where the hippocampus is getting its information from to help you learn so if you destroy neurons in the entorhinal cortex you have less input to the hippocampus and youre less able for learning and memory)
- –> Neurodegeneration spreads outwards, and extends into the cerebral cortex, as disease progresses
– Newer memories are more dependent on the entorhinal cortex and hippocampus rather than older memories which is why many alzheimers patients forget recent memories but still have their childhood memories. It is thought that long-term memories are stored in the anterior cingulate cortex and over time become less dependent on the hippocampus/entorhinal cortex
How do neuritic plaques form in AD?
- Neuritic plaques are composed of a central core of homogenous protein called b-amyloid
- b-amyloid is a product of the amyloid precursor protein (APP) gene; found on chromosome 21
- Misfolded b-amyloid proteins aggregate to form dense, insoluble deposits in the synaptic cleft
- —> APP has a short intracellular and long extracellular component in the membranes at the synapse. APP is implicated in synapse formation and synaptic plasticity; which are important for learning and memory. Proteolysis product is the b-amyloid protein; Enzymes chop up the extracellular component of the APP molecule to form beta-amyloid (small fragments of the APP molecule). Over time these b-amyloids stick to each other and form these big insoluble deposits in the extra-cellular space
- Plaques starts in the entorhinal cortex and spreads to the basal forebrain/medial temporal lobe and eventually it spreads to all over the cerebral cortex and cortical thinning results
- the b-amyloid plaques in the synaptic terminal make it hard for these NT to bind to and activate the post-synaptic cell. This prevents one neuron from communicating with the other neuron, resulting in cell death because the neuron does not get the neurotrophic factors (nutrients that help that neuron grow) from neuron B (the post-synaptic neuron) resulting in atrophy (as seen in Alzheimer’s patients) because the neuron is choked from their circuit
What is the cytoskeleton and what are the three main types?
- Cytoskeleton is the evolutionary solution to maintaining a neurons 3D structure (as well as guiding the transport of proteins and molecules across vast distances.)
- Cytoskeleton functions as both flexible scaffold and transportation system.
1. Neurofilaments – control & transport of membrane proteins;
2. Microtubules – control the transfer/movement of substances and organelles throughout the cytoplasm;
3. Microfilaments – provides structural support to axons & dendrites.
- Cytoskeleton functions as both flexible scaffold and transportation system.
What are tau proteins?
- Tau proteins are involved in the stabilization and flexibility of microtubules and microfilaments.
- –> Highly soluble protein; dissolved in water (goes into solution very easily) which is great because when things are insoluble they precipitate (form clumps) which is obviously not good.
- –> Activated through phosphorylation; adding a phosphate group
- –>Promote the assembly of microtubules; these Tau proteins float around the cytoplasm in solution until we need to build a microtubule in which these Tau proteins phosphorylate (adding a phosphate molecule causing it to come out of solution) which will then be put together to create these microtubules
- kinesin proteins; carry things by burning a molecule of ATP and taking a step and then burning another molecule of ATP and taking a step (will physically walk things down the cytoskeleton to get things from the soma to the axon terminal)
How do neurofibrillary tangles form?
- Hyperphosphorylated tau proteins begin to accumulate, eventually forming aggregates (neurofibrillary tangles) inside cell bodies.
- this begin to accumulate over time which causes causes these tau proteins to not “click” into place to form these microtubules in the first place
- these tau proteins phosphorylate to form microtubules every time a kinesin protein “walks” on it and after the kinesin protein delivers the tau proteins dephosphorylate and go back into solution. In alzheimers, they become hyperphosphorylated and can never go back into solution and over time it forms this clump causing the microtubules to disintegrate
- As a consequence, microtubules disintegrate and ultimately destroy the structure of the cytoskeleton (major collapse to neurons transport system)
- Malfunctions in biochemical pathways and communication between neurons; this is because it can’t transport NT or other substances from the soma to terminal buttons. Even if it could, b-amyloid plaques will prevent these NT to move across cleft and activate post-synaptic neuron)
- Eventually leads to cell death.
What increases risk of developing AD?
– Twin studies suggest between 49% - 79% heritability.
(Several genes are implicated in AD)
– Acute exposure to, and poisoning from, heavy metals and pesticides is a known risk for AD.
– Recent evidence is beginning to show that chronic, low-level exposure to these toxins also leads to neurodegeneration.
– Air pollution, especially in large, urban cities, is a cocktail of organic and non-organic compounds, metals and gases that can be toxic
How can you manage/treat Alzheimer’s disease?
- drugs that increase acetylcholine neurotransmission have been shown to improve cognitive symptoms of AD.
- —> Exelon is a cholinergic agonist (can bind to the acetylcholine receptors and activate it) that appears to provide temporary relief from the progression of AD;
- —>Available orally or via transdermal patch.
- Consuming more choline in the diet is theoretically sound, however has yet to yield positive empirical results.
- —> There is a ceiling amount of ACh produced and stored by neurons, they do not stockpile ACh or produce superfluous amounts (only enough to get through day/week)
- —>Eating a choline rich diet may protect/delay the onset of AD particularly in those that have a poor choline diet
