Alzheimer's Disease Flashcards

Question

Describe the senile plaques in AD

Answer 1

This happens in AD, where the β-amyloid aggregates are dumped outside the neurons, but it doesn’t seem to correlate with symptoms; there’s probably a threshold for this. A classic plaque is seen as a condensed Aβ in the centre, a halo, and then a ring of Aβ (red). It is a sign of advanced disease. Whereas in early disease we see a more diffuse plaque (green).

Answer 2

Pretty much most people over the age of 60 will have plaques and tangles, so how to define Alzheimer’s?. Need to know amount and location – a threshold before symptoms are reached. * Stage I: earliest stage is in the entorhinal cortex in the medial temporal lobe, next to the anterior hippocampus. * Stage II: massive increases in parahypocampus gyrus and starting to appear in posterior hippocampus * Stage III: florid pathology throughout the hippocampus * Stage IV: gets into other hippocampus (this is important because at this stage you start to get cognitive deficits * Stage V: occipital cortex (peristriatal cortex) * Stage VI: striatal cortex The first three stages are pre-symptomatic. There are 10-15 years where people are asymptomatic. People only affected in these stages show “mild cognitive impairment”, aka MCI. The pathology starts in the anterior hippocampus, then progresses to the posterior hippocampus, transentorhinal cortex of the hippocampus (where the 6 layer structure of the hippocampus turns into a 3 layer structure) then progresses through the temporal lobe. Then you see pathology in the occipital cortex and the primary motor cortex.

Answer 3

APP (amyloid precursor protein) is a membrane protein with an unknown primary function, but important in synapse formation, neuronal plasticity and iron export. Usually, APP is transcribed in the endoplasmic reticulum, and moves to the Golgi, and then it moves into secretory vesicles to the cell surface.

Answer 4

Usually, APP is transcribed in the endoplasmic reticulum, and moves to the Golgi, and then it moves into secretory vesicles to the cell surface. In the secretory vesicles or at the cell surface, it can be cleaved by alpha-secretase to release soluble APP extracellularly. * It can be endocytosed from the cell surface (with or without being cleaved by alpha secretase) and then cleaved by either β-secretase or gamma-secretase within the endosomes. * If cleaved by alpha and then gamma secretase (non-amyloidogenic pathway), then it’s degraded in lysosomes [good]. α-secretase cleavage can happen in golgi, vesicles and cell surface membrane . * If cleaved by beta and then gamma secretase (amyloidogenic pathway), it generates a APP-β monomer, which then polymerises to form oligomers, protofibrils and eventually fibrils. o Most of β-secretase cleavage happens in endosomes

Answer 5

Our best hypothesis so far, even though people know it's not completely right (even John Hardy himself) is the amyloid cascade hypothesis. It is though that the intracellular Aβ oligermers, protofibrils and fibrils lead to the hyperphosphorylation of tau.

Answer 6

The strongest evidence for Aβ as a causative agent in Alzheimer's Dementia is the mechanism behind familial AD. There are three main genes implicated in familial AD: * APP (chromosome 21) - codes for Amyloid Precursor Protein. Mutations usually affect cleavage by secretase enzymes. Some make cleavage sites more accessible, other mutations make cleavage harder. * Presenilin 1 (chromsome 14) * Presenilin 2 (chromsome 1) * Both PSEN1 and PSEN 2 provide the catalytic subunit of the gamma secretases. Mutations in these leads to the formation of longer, more hydrophobic Aβ peptides. Mutations in tau tend to cause frontotemporal dementias not AD, though there can often be Aβ pathology as well.

Answer 7

The mechanisms of normal Aβ clearance: * Enzymes that degrade Aβ - IDE (insulin degrading enzyme) * Clearance mechanisms through chaperones * Degradation through microglia * Can use LRP to transport Aβ out of the brain; then it can be degraded in the liver and kidney or can be re-internalised by RAGE receptors * Another mechanisms of clearance is by glial cells

Answer 8

* Stop aggregation of Aβ * Clear Aβ deposits (vaccine, neprilysin) * Alter metabolism of APP * Anti-inflammatories. People on anti-inflammatory drugs (e.g. for rheumatoid arthritis) have a decreased risk of AD (but terrible GI side-effects, so not great as a prophylactic treatment) * Growth factors * Tissue transplants

Answer 9

* Shift to non-amyloidogenic pathway by increasing the expression of α-secretase. * Inhibit the expression of β-secretase by inhibiting the BACE1 gene. * Rosiglitazone showed promise in phase II trials, but did not show a significant effect in phase III trials (Gold et al 2010)

Answer 10

* Immunisation - one trial of vaccine against f Aβ-42 showed promise in animal models. However was stopped at Phase II as 18 patients developed meningioencephalitis. * Though patients had been cleared of Aβ pathology and showed cognitive improvements, the approach made no difference in terms of survival - so disease course was unaffected. * However, this could be because of starting the therapy too late (20 years of Aβ build-up before symptoms), and also they found that 25% of patients didn't even have AD. Some had tauopathies, vascular dementia etc. * Antibodies such as aducanzumab appear to clear Aβ, and slow cognitive decline. Phase 3 trials are still awaiting. Clearing of Aβ was dose-dependent, and measured by PET scans. * Side-effects on the antibodies include oedema, and frank haemorrhages.

Answer 11

* Growth factors delivery to the brain? Unfortunately many do not cross the BBB * New trials use gene therapy to get growth factors into the brain * Anti-inflammatory drugs. High dose NSAIDs has been shown to reduce the risk for AD. The patients that take these usually have Rheumatoid Arthritis. It is thought NSAIDs have a variety of targets to produce this neuroprotective effect. * However, clinical trials have not produced satisfactory results. This may be because the trials only go for one year, whereas RA patients have been taking NSAIDs for many years.

Answer 12

* To confirm/test hypotheses regarding aetiology and pathophysiology. Animal models had been used to confirm the role of Aβ in familial cases of AD involving the APP and Presenilin genes. This has opened a whole subject of understanding around the pathophysiology of Alzheimer’s disease, with Aβ most-likely playing an important role. This ultimately leads to treatment **target identification** and **target validation**. * To test new treatments after in-vitro studies. It is one thing finding a compound which clears Aβ in vitro, and it is another to see if this translates to dynamic nervous systems, and whether this leads to any improvement in function.

Answer 13

* Animals such as **monkeys, dogs** and **dolphins** have been known to develop Aβ plaques in nature. However, not only are larger mammals difficult to work with and have long natural life-spans, there are greater ethical concerns with their experimental use. Therefore, rodent models are more commonly used even though they do not develop Aβ plaques. * To get around this we create transgenic mice that express **double** **or** **triple** **mutations** in genes implicated in familial AD, such as APP. Transgenic tau animals do not produce neurofibrillary tangles. But **intracerebral injection** using **AAV vectors** in wild type mice can cause tangles. It also allows you to recreate various stages of amyloid pathology.

Answer 14

* Rodent models have been used to confirm the role of the **Familial** **AD** **genes** and confirm the role of **lipid** **metabolism** and **inflammation** in AD pathology amongst most AD pharmacological testing. They usefully share pathological features of AD such as **Aβ** **plaques**, **neurofibrillary tangles**, synaptic loss, glial pathology and astrogliosis, however do not show significant neuronal loss as seen in human AD.

Answer 15

* Advantages: * Brain anatomy similar to humans * NFT and plaque staging, regional vulnerability can be addressed * Sophisticated behavioural tests possible * Therapeutic treatments possible, monitored by histopathological and behavioural tests. * Disadvantages: * Production and breeding of transgenic mice is laborious and expensive * Ethical considerations limit animal number and prohibit certain experiments * High throughput drug screening not possible.

Answer 16

* **Morris water maze** - to see if they remember where the platform is in the swimming pool. * **Y maze** - to see if they remember which direction of the Y to go in * **Radial maze** - to see if they go through each of the radial arms only once or more times to find food. * **Object recognition** - to see if they move from the circle to the triangle. Mice that have cognitive problems spend the same amount of time with new and old objects because they have forgotten the familiar object.

Answer 17

* **Sea lamprey** (**P. marinus**) has been used to observe the sequence of tau degenerative sequences. It’s main advantage it’s well characterised ABC giant neurones which can be microinjected with tau. * **Nematode** (**C. elegans**) has been useful to isolate AD-specifc genes as well as monitor behavioural and synaptic abnormalities. Advantages include: * Easy, cheap, and fast to breed * No ethical limitations * Powerful genetics, and RNA interference allows inactivation of thousands of genes in parallel * Drug screening possible * **Drosophilia** (D. **melanogaster**) has been used for the analysis of the physiological role of APP, with implications for pathological role such as impaired axonal transport. Advantages include: * Easy, cheap, and fast to breed * No ethical limitations * Powerful genetics, and RNA interference allows inactivation of thousands of genes in parallel * Drug screening possible

Answer 18

* **Disadvantages** of the three aforementioned animal models include: * Different brain anatomy * Behavioural abnormalities of AD difficult to assess * NFT and plaque staging and regional vulnerability impossible to address.

Answer 19

* In advanced Alzheimer’s disease, there’s a reduced volume of the brain, especially in the hippocampus * Some areas involving language or memory are particularly affected, for example Wernicke’s area and the hippocampus * The sulci are larger and the gyri are reduced * You can see this on a brain slice or in a structural MRI * You can also see medial temporal lobe atrophy and grey matter differences (volume loss) in AD

Answer 20

* Biomarkers Of Brain Function (Glucose Metabolism) 18F-FDG PET in AD * Amyloid plaques: 11C-PIB * Activated microglia: 11C-PK11195

Answer 21

* There are decreases in glucose metabolism in AD patients compared with normal controls; this can be seen by statistical parametric mapping and in 18F-FDG PET. This statistically significant decrease seen in: * Temporal, Parietal, Occipital and Posterior Cingulate areas. * But not in Anterior cingulate, Thalamus, Striatum or Frontal. * People with ApoE4 (but no dementia) already have a small functional deficit in these areas

Answer 22

11C-PIB selectively binds to fibrillary amyloid and has a high intensity on PET imaging in AD patients. * This can also be seen in statistical parametric mapping * There are significant increases in 11C-PIB binding in AD * The temporo-parietal and frontal areas are most affected * Amyloid deposition is mostly found in the cortical areas. The cerebellum is devoid of fibrillar amyloid.

Answer 23

You can also see increased 11C-PIB in MCI (50% retention), but not as high as AD (82% retention). PIB-positive subjects with mild cognitive impairment (MCI) are significantly more likely to convert to AD than PIB-negative patients, faster converters having higher PIB retention levels at baseline than slower converters. * In vivo detection of amyloid deposition in MCI with PIB PET provides useful prognostic information * There’s a 20% increase in PIB-positive MCI at the end of follow-up * The clinical conversion to AD is 75% in PIB-positive MCI during a 12-30 month follow up

Answer 24

Using 11C-PIB PET imaging. Amyloid deposition is an early event. It is stable in AD with increased retention. So while amyloid deposition remains stable, over the same amount of time, the patient's memory scores can decrease significantly. Amyloid presence is not specific to Alzheimer's disease, as amyloid is present in other neurodegenerative diseases such as Lewy Body Dementia. In fact, there is more amyloid in LBD than in Alzheimer's Dementia.

Answer 25

PET scan looking at activated microglia. You can use 11C-PK11195 binding to TSPO translocator protein in activated microglia in AD. Amyloid (11C-PIB) binding is not correlated to disease progression. Amyloid deposition occurs early and remains stable while memory impairement worsens.

Answer 26

You can use 11C-PK11195 binding to TSPO translocator protein in activated microglia in AD * There is more binding of 11C-PK11195 in AD patients * This can also be seen in Voxel analysis (parametric statistical analysis) * This correlates with a decrease in MMSE scores * Amyloid plaque load (measured by 11C-PIB) correlates with microglia activation (measured by 11C-PK11195) and there’s an overlap between PIB and PK11195 in PET imaging * There’s increased baseline PK binding in 38% of MCI cases

Answer 27

Evidence: * Contamination of growth hormone extracts induced CJD: When pituitary glands were extracted and pooled, and then homogenised and injected into brains, after 30 years, they found CJD and Aβ deposits in the patient. (But actually the patients didn’t develop Alzheimer’s disease, they just saw Aβ deposits). You can also see the induction and spread of Aβ lesions in a transgenic mouse models. * Parabiosis studies have also shown that sharing circulation with another animal allows the 'transmission' of Aβ. * Rodent AD models can be induced by injecting human Aβ-rich brain extracts. They form senile plaques and CAA. * Aβ fibril seeds can also induce animal models of AD.