Neurodegeneration and Alzheimer's Disease

Question 1

What is neurodegeneration?

Answer 1

The progressive loss of function/structure of neurons and neuronal death

Question 2

What are the common factors of neurodegenerative diseases?

Answer 2

Involved with ageing, causes and pathogenic mechanisms largely unknown except Huntingtons and other rare familial conditions, they’re progressive diseases, there’s no cure (drugs only treat symptoms), characterised by common features eg accumulation and aggregation of specific proteins, mt damage, glial activation, etc

Question 3

How are these diseases often classified?

Answer 3

On the basis of the location of the characteristic lesions ie. Amyotrophic Lateral Sclerosis aka. upper motor neuron disease (motor cortex) or lower (anterior horn of spinal cord or cranial nerve motor nuclei)

Question 4

What is ataxia?

Answer 4

Ataxia is the loss of control and coordination of voluntary movement

Question 5

Which diseases are often the result of neurodegeneration in the cerebellum?

Answer 5

Olivo-ponto-cerebellar degeneration and Freidrich’s ataxia

Question 6

What are the characteristics of cerebellar neurodegeneration disorders?

Answer 6

Disturbances in gait, balance, speech, eye movements but no weakness. Also sufferers of ataxia may not be able to heel toe walk, stand on one leg, evaluate the right force direction and distance of movements

Question 7

What is the cause of Freidrichs ataxia?

Answer 7

A recessive mutation in the mitochondrial protein frataxin. The cerebellar nuclei and sensory spinal structures have lesions which leads to the wide legged, unsteady, lurching walk

Question 8

Which diseases involve neurodegeneration in the basal ganglia?

Answer 8

Parkinson’s and Huntington’s disease

Question 9

Describe the region of the brain responsible for Parkinson’s disease and the pathology

Answer 9

Selective dopaminergic neuron loss in the substantia nigra pars compacta. This leads to slow stiff movements hindered by tremor which eventually cease

Question 10

Describe the region of the brain responsible for Huntington’s disease and the pathology

Answer 10

Presents with involuntary, uncontrolled, exaggerated movements known as chorea. The cause is repeated CAGs (glutamine) in the Huntingtin gene which causes misfolding of protein that leads to GABAergic neuron death in the corpus striatum

Question 11

How do neurons degenerate?

Answer 11

Acute injuries may lead to necrosis, where the cells can’t maintain their membrane integrity and ion gradients and release their contents -> inflammation. However, neurodegen. progresses slowly over the years with no evidence of necrosis. It’s thought that excessive PCD (apoptosis or autophagy) is the cause

Question 12

What is dementia?

Answer 12

The progressive loss of memory and atleast one other cognitive domain, severe enough to interfere with everyday tasks. Many disorders are accompanied by dementia, which can be reversible (alcohol induced/medication) or irreversible (neurodegeneration)

Question 13

What is dementia caused by and what does it effect?

Answer 13

Neurodegeneration in the cerebral cortex leading to impairment of higher cognitive functions eg. memory, spatial awareness, language, personality, judgement, emotions, abstract thought

Question 14

What is mild cognitive impairment?

Answer 14

When complex (not simple) every day task performance is affected. Can be an early manifestation of dementia.

Question 15

What is the most common cause of dementia?

Answer 15

Alzheimer’s disease, which is cortical neurodegeneration with a specific pattern of pathological features and accounts for 50-80% of dementia cases.

Question 16

What are the other common types of dementia?

Answer 16

Vascular (multi infarct) - 2nd most common, typically caused by many small strokes
Dementia with lewy bodies (aggregated protein accumulation)
Frontotemporal neurodegeneration - characterised by loss of language and behavioural change in a relatively young population
Dementia associated with some cases of PD or HD

Question 17

What are the pathological hallmarks distinguishing Alzheimer’s disease from other forms of dementia/

Answer 17

Microscopic deposits inside and outside the cortical neurons.

Question 18

What are the first signs of demetia?

Answer 18

Often impairment of recent declarative memory, indicating pathological lesions in the medial temporal lobe. In the early stages, memories of the remote past are preserved

Question 19

How does dementia progress?

Answer 19

Impairment of recent declarative memory. Then, other cognitive functions gradually decline, leading to becoming lost in familiar places, forgetting the meanings of words and uses of common objects, loss of language completely, forget family members, confused, agitated, aggressive

Question 20

What is amyloid?

Answer 20

Amyloid is the protein constituting the neuritic (senile) plaques. Called amyloid beta as secondary structure is rich in B pleated sheets. They stick together to make fibrils, then causing large insoluble filaments

Question 21

What is the mechanism of action of AB proteins causing senile plaques?

Answer 21

AB monomers turn into AB soluble oligomers, which are thought to be more harmful as they impair basic neuronal processes (communication) well before clinical presentation. It is thought that the plaques are a protective mechanism against the more harmful form of AB

Question 22

What happens to the neurons surround AB plaques?

Answer 22

Neuronal dendrites and glial processes around the plaques appear abnormal and are surrounded by activated microglia - a sign of inflammation

Question 23

How does Tau protein contribute to neurofibrilliary tangles?

Answer 23

They are intracellular inclusions caused by large aggregates of paired helical filaments made from tau protein. Normally, tau proteins bind to microtubules, stabilising them. When tau is abnormally hyperphosphorylated, microtubule affinity is decreased. Tangled clumps of tau protein impair neuronal function via obstructing axonal transport and intracellular transport mechanisms

Question 24

How is Alzheimer’s disease diagnosed?

Answer 24

There is not a reliable non invasive marker of AD, so it is diagnosed on clinical symptoms, and confirmed by the presence of plaques and tangles on autopsy

Question 25

Which neurons do the lesions present in AD affect?

Answer 25

The lesions are accompanied by neuronal and synaptic loss, selectively affecting cortical pyramidal neurons, starting at entorhinal cortex and hippocampus, spreading to prefrontal posterior parietal and temporal lobe, and amygdala.

Question 26

What do neuronal and synaptic loss lead to?

Answer 26

Brain atrophy, ie. thinning of gyri and widening of sulci and cerebral ventricles.

Question 27

Which part of the basal ganglia is affected by Alzheimer’s disease?

Answer 27

Nucleus Basalis of Meynert is a structure in basal forebrain that sends widespread cholinergic projections to neocortex, playing a role in cortical excitability, conscious awareness, attention, memory. It is selectively vulnerable to AD lesions. The selective loss of cholinergic neurons was thought to be a cause of AD but it’s a downstream effect.

Question 28

What is the amyloid hypothesis?

Answer 28

It is the prevalent theory that an imbalance in AB production and clearance leads to an accumulation of AB and hence neurofibrillary tangles and neuronal dysfunction and death

Question 29

Describe amyloid processing

Answer 29

Amyloid precursor protein is normally cleaved by a and y secretases, generating APPsa (neuroprotective) and 2 other peptides of unknown function. This is non-amyloidogenic processing.
Amyloidogenic processing is when APP is cleaved by b-secretase, then y secretase. Usually, only a small amount of AB is produced, but in AD it is present in much larger amounts. AB can be 39-42aa long, most common normal type is AB-40, in AD plaques its AB-42 which aggregates more easily and is more toxic

Question 30

Which genes are responsible for 1-5% of AD cases that are early onset and dominant?

Answer 30

Mutations in APP, presenelin 1, and 2. APP mutations increase the amount of AB generated. Presenilins are components of y secretase, and mutations in them lead to the production of more AB-42 than 40.

Question 31

Which mutations result in a decreased likelihood of getting AD?

Answer 31

Carriers of an APP missense mutation in the AB region that results in decreased APP cleavage by B secretase (generating a non-aggregating mutant AB)

Question 32

What is the link between Down’s syndrome and dementia and amyloid plaques?

Answer 32

Down’s sufferers often develop dementia and amyloid plaques as early as 30s, because they have 3 chromosome 21s and this is where the APP gene is

Question 33

What is the biggest risk factor for sporadic Alzheimer’s disease? (Excluding age)

Answer 33

Apolipoprotein E genotype, the main apolipoprotein in the CNS. It has 3 polymorphisms, E2, 3, 4 (8, 75, 15% frequency). E4 carriers have up to 20x risk of developing AD, compared to E3/E2(may be protective) carriers

Question 34

How does increased levels of ApoE4 contribute to AD?

Answer 34

Not known, theories include differentially binding AB, inhibiting AB clearance via proteolytic enzyme inhibition, removal across blood brain barrier, increasing AB generation via B-secretase activity, increasing AB aggregation. It’s also been found to affect Tau aggregation

Question 35

Which other factors confer a degree of risk of developing AD?

Answer 35

Genes involved in inflammation and microglial activation, cholesterol metabolism, regulation of endocytosis

Question 36

How can anticholinergics be used to treat AD

Answer 36

Acetylcholinesterase inhibitors allow Ach to be in the synapse for longer, counteracting the loss of cholinergic neurotransmission which is present in AD. Donepezil, galantamine, rivastigmine

Question 37

How can memantine be used to treat AD?

Answer 37

It is a glutamate NMDA receptor inhibitor. Theyre excessively activated in neurodegenerative disorders which lead to neuronal death, termed excitotoxicity. Given alone or with anticholinergics

Question 38

What are some future developments for the treatment of AD?

Answer 38

Immunotherapy - monoclonal ABs used to target AB or AB vaccination
B-secretase inhibtiors, y-secretase inhibitors, AB aggregation inhibitors. At late stage AB may not be an appropriate target because toxic cascade has begun
Target Tau aggregation and reducing neuroinflammation
Brain training, exercise, sleep, healthy BP to reduce risk