Neurodegenerative disease

Question 1

Explain the basic concepts of neurodegeneration

Answer 1

Neurodegeneration refers to the progressive loss of structure or function of neurons, including the death of neurons

1) Neuron Vulnerability:

• Not all neurons are equally vulnerable to degeneration, and different neurodegenerative diseases affect different sets of neurons
• E.g. Parkinson’s disease affects primarily the dopamine-producing neurons in a part of the brain called the substantia nigra

2) Protein Misfolding and Aggregation:

• A common feature of many neurodegenerative diseases is the accumulation of misfolded proteins
• In Alzheimer’s, for instance, there is an abnormal accumulation of beta-amyloid plaques outside neurons and tau tangles inside neurons
• These misfolded proteins can cause a toxic gain of function or a harmful loss of function, contributing to neurodegeneration

3) Genetics and Environment:

• Both genetic and environmental factors contribute to neurodegenerative diseases
• E.g. certain genetic mutations have been linked to early-onset forms of Alzheimer’s and most cases of Huntington’s
• Environmental factors such as exposure to toxins or traumatic brain injury can also contribute to neurodegenerative diseases

4) Oxidative Stress and Mitochondrial Dysfunction:

• These processes contribute to neuronal damage and death in many neurodegenerative diseases
• Neurons are particularly vulnerable to oxidative stress due to their high metabolic activity and comparatively low levels of antioxidant defenses

5) Inflammation:

• Neuroinflammation often accompanies neurodegenerative disease

6) Apoptosis:

• in many neurodegenerative diseases, neurons die by apoptosis
• However, the triggers for apoptosis in these diseases are varied and can include genetic factors, mitochondrial dysfunction, oxidative stress, and excitotoxicity (a pathological process by which nerve cells are damaged and killed by excessive stimulation by neurotransmitters)

Question 2

Explain the symptoms and pathology of Alzheimer’s disease and Parkinson’s disease

Answer 2

Alzheimer’s Disease (AD):

Symptoms:

1. Memory loss that disrupts daily life, especially forgetting recently learned information
2. Challenges in planning or solving problems
3. Difficulty completing familiar tasks at home, at work, or at leisure
4. Confusion with time or place
5. Trouble understanding visual images and spatial relationships
6. New problems with words in speaking or writing
7. Misplacing things and losing the ability to retrace steps
8. Decreased or poor judgment
9. Withdrawal from work or social activities
10. Changes in mood and personality

Pathology:

1. Amyloid plagues are essentially clumps of beta-amyloid, a fragment of the amyloid precursor protein (APP). Mutations in the genes for APP and other proteins can lead to an overproduction of beta-amyloid fragments
2. Neurofibrillary tangles are tangles of hyperphosphorylated tau protein. Normally, tau helps to stabilise microtubules, which are an essential part of the cell’s cytoskeleton. In AD, abnormal tau proteins form threads that eventually join to form tangles inside neurons, disrupting the cell’s transport system and harming synaptic communication between neurons

Parkinson’s Disease (PD):

Symptoms:

1. Tremor, mainly at rest and described as pill rolling tremor in hands.
2. Bradykinesia (slowness of movement).

3 Limb rigidity.

4. Gait and balance problems.
5. Loss of automatic movements (like blinking, swinging arms while walking).
6. Speech and writing changes.
7. Non-motor symptoms can also occur and include cognitive changes, mood disorders, sleep problems, constipation, loss of smell, and orthostatic hypotension

Pathology:

Loss of dopaminergic neurons in the substania nigra (reward and movement)

his loss leads to a reduction in the level of dopamine, a neurotransmitter that helps regulate movement, mood, and reward

1. Lewy bodies: These are abnormal aggregates of protein that develop inside nerve cells in Parkinson’s disease. They are characterized by the presence of alpha-synuclein, a protein found widely in the brain with functions related to the release of neurotransmitters
2. Neuroinflammation: Activated microglia, the immune cells of the brain, are found in PD brains suggesting a role for inflammation
3. Oxidative Stress: The brain uses a lot of oxygen and produces potentially harmful by-products called reactive oxygen species, which can cause cell damage (oxidative stress)

Question 3

Explain the principle causes of these conditions, and the fact that they are usually idiopathic but can also be monogenic in nature

Answer 3

AD:

Idiopathic Causes:

• The majority of Alzheimer’s cases are late-onset (typically developing after age 65) and appear to result from a complex mix of genetic, environmental, and lifestyle factors
• These factors lead to a buildup of beta-amyloid plaques and tau tangles in the brain, which cause neuronal damage and the symptoms of Alzheimer’s

Monogenic Causes:

• A smaller proportion of cases, often referred to as early-onset Alzheimer’s disease, are inherited in a simple, Mendelian fashion, and these are caused by mutations in one of three genes
• the APP gene, presenilin 1 (PSEN1), or presenilin 2 (PSEN2)
• These mutations lead to an overproduction of the beta-amyloid fragment of APP, leading to the accumulation of plaques

PD:

Idiopathic Causes:

• A variety of risk factors have been identified, including age, exposure to certain toxins, and male gender
• It is believed that in these cases, there is a complex interplay between genetic predisposition and environmental factors

Monogenic Causes:

• include the SNCA gene (which codes for the alpha-synuclein protein), the LRRK2 gene (leucine-rich repeat kinase 2), the Parkin gene, PINK1, DJ-1
• These genetic forms of PD often, but not always, have an earlier onset

Question 4

Explain the idea (as an extension of the above) that Alzheimer’s disease and Parkinson’s disease are not single conditions

Answer 4

AD:

AD is commonly thought of as a single condition characterised by memory loss and cognitive decline. However, we now understand that Alzheimer’s represents a spectrum of disorders with varying presentations. Not all patients experience the same symptoms or progress at the same rate

One important factor in this variability is the existence of different subtypes of Alzheimer’s disease, which can present with different initial symptoms and have different patterns of symptom progression

For example, some patients may initially present with language problems, visual issues, or issues with judgement or problem-solving, rather than memory loss. These forms of Alzheimer’s are often termed “atypical Alzheimer’s”

PD:

PD is traditionally defined by its motor symptoms: bradykinesia, resting tremor, rigidity, and postural instability

However, there is now recognition of a broad array of non-motor symptoms that can occur in PD, such as cognitive impairment, depression, sleep disorders, and autonomic dysfunction

Moreover, there are several genetic forms of PD (caused by mutations in genes like LRRK2, PARK7, PINK1, etc.) that may present with somewhat different phenotypes

Question 5

Explain the interplay between neurodegeneration and neuroinflammation, and how ageing can affect this

Answer 5

Neurodegeneration and Neuroinflammation:

Neurodegeneration refers to the progressive loss of structure or function of neurons, including their death

Conditions such as Alzheimer’s and Parkinson’s disease are characterized by this progressive neuronal loss

Neuroinflammation, on the other hand, is the inflammatory response within the brain or spinal cord

This response is usually beneficial and helps to protect the brain from infections and injuries

It’s mediated by microglia and astrocytes, the brain’s resident immune cells

However, when neuroinflammation becomes chronic or excessive, it can contribute to neurodegeneration

Prolonged inflammation can lead to a toxic environment for neurons, damaging these cells and leading to their dysfunction and eventual death

This is largely due to the release of pro-inflammatory cytokines and other substances that can be harmful to neurons

The Role of Ageing:

Ageing is a major risk factor for neurodegenerative diseases.

As we age, several changes occur in the brain that can exacerbate both neurodegeneration and neuroinflammation

1) Chronic Low-grade Inflammation:

• With age, the immune system undergoes a process known as “immunosenescence,” becoming less effective at fighting off infections and more prone to low-grade, chronic inflammation
• This can increase the levels of inflammation in the brain, contributing to neuroinflammation

2) Cellular Damage:

• Ageing also brings about an accumulation of cellular damage due to factors like oxidative stress and the failure of cellular waste disposal mechanisms
• These can lead to neuronal dysfunction and death, driving neurodegeneration

3) Microglial Senecence:

• Microglia, the primary immune cells in the brain, also undergo changes with age.
• They can become “senescent,” which means they’re less effective at their normal functions and can also contribute to chronic inflammation

4) Blood-Brain Barrier Breakdown:

• Ageing can also lead to increased permeability of the blood-brain barrier, allowing more immune cells and possibly pathogens from the periphery to enter the brain, contributing to neuroinflammation