Neurodegenerative Diseases

Question 1

Intro to lecture

Answer 1

Whereas neural tube closure defects and the like are failures to properly assemble the nervous system, neurodegenerative diseases are the consequence of failure to maintain these structures. As you will see, neurodegeneration can begin from birth, but, more often than not, neurodegenerative diseases are diseases of the elderly. In a world with an increasing population size and increasing longevity, understanding age-related neurodegenerative diseases like Alzheimer’s disease and Parkinson’s disease is of growing importance.

Question 2

What is neurodegeneration and neurodegenerative disease?

Answer 2

Neurodegeneration = neuro (relating to neurons) + degeneration (progressive loss)

Neurodegenerative disease = any disease caused by neurodegeneration

Question 3

What are some basic details about neurodegenerative disease?

Answer 3

Affect the CNS or PNS (or both)
Begin at any stage of life
The most common ones are associated with ageing
Rarer types of neurodegenerative disease start in childhood or even from birth
Earlier age of onset = greater genetic contribution
Later age of onset = more likely a sporadic (or idiopathic) disease

Neurodegenerative diseases are highly heterogeneous

Some disease names are really umbrella terms Conditions with overlapping phenotypes, but distinct causes (e.g. at least 25 types of SCA from mutations in different genes)

Some diseases are inherently pleiotropic. Symptoms manifest differently in different people(e.g. Parkinson’s disease symptoms unique to individual)

Question 4

What do common features of neurodegenerative diseases include?

Answer 4

Many follow a similar pattern:

1. Molecular impairment somewhere in the cell
2. Decreased transmission at synapse
3. “Dying back” of neurites (axons and/or dendrites)
4. Cell death

and diseases frequently involve:

Protein aggregation (“proteinopathies”)
Lysosomal dysfunction
Mitochondrial dysfunction
Associated inflammation via activation of glia

Question 5

What is Alzheimer’s disease?

Answer 5

The most common neurodegenerative disease and the most common cause of dementia
Onset is usually >65 years of age, but ~10% are “early onset” starting ~30s onwards
Incidence:
10% of people aged 65+
50% of people aged 85+
AD is NOT a normal part of ageing – it is a disease

Question 6

What is dementia as an umbrella term?

Answer 6

A decline in memory and other cognitive functions that impair quality of life
Impairments in dementia are distinct from “normal” cognitive lapses, e.g.
getting lost in their own neighbourhood
not recognising a family member etc

Normal ageing = gradual decline in normal cognition, gradual changes in personality

Question 7

What are pathological hallmarks of Alzheimer’s?

Answer 7

Brain shrinkage

Proteinopathies:
Amyloid plaques
they are Extracellular protein aggregates
they are Enriched in Aβ peptides

Neurofibrillary tangles:
Also called paired helical filaments
Intracellular protein aggregates
Enriched in Tau protein

Question 8

What is Abeta peptide?

Answer 8

Aβ peptide is cleaved from a transmembrane protein called amyloid beta precursor protein (APP) by proteases

Mutations to three proteins involved in Aβ peptide processing are known to cause rare early onset forms of Alzheimer’s:
APP
PSEN1
PSEN2

Since early 1990’s “Amyloid hypothesis of AD”, which states that Aβ and/or amyloid plaques are the cause of AD

Question 9

What does Tau normally bind?

Answer 9

Tau (an intracellular protein) normally binds microtubules in axons
Hyperphosphorylated tau is displaced causing:
Tangles
Destabilised microtubules

Question 10

What 3 main roles do microtubules have?

Answer 10

1. Structure/shape of cell
2. Positioning of organelles
3. Motorways for transporting vesicular cargo

Question 11

In typical late onset AD (i.e. not genetic forms of AD), neurofibrillary tangles are:

Answer 11

Seen before amyloid plaques
Well correlated with cell death and progression

The Tau hypothesis suggests Tau is upstream Aβ = Tau hypothesis

Question 12

So is the Tau or Amyloid hypothesis the real one?

Answer 12

We don’t know! Still very controversial!

Question 13

What are some other risk factors for Alzheimer’s disease?

Answer 13

Down syndrome (APP is on chromosome 21)
Gender (more common in women)
High BP, Cardiovascular disease, Diabetes
Low education
Head injury
Smoking and drinking
Only a small genetic risk contribution for late-onset AD (APOE gene status most significant)

Question 14

What is Parkinson’s disease?

Answer 14

The second most common neurodegenerative disease
Onset is usually 60-65 years of age, but ~10% start before 45 years of age
Lifetime risk:
Males ~2%
Females ~1.3%
Like AD, Parkinson’s disease is incurable

Question 15

What do symptoms of Parkinson’s disease include?

Answer 15

A movement disorder, with four ‘cardinal’ features:

1. Resting tremor
2. Bradykinesia (slow movement)
3. Rigidity
4. Postural instability (fall over)

>90% of patients display additional NON-MOTOR symptoms, including:
Depression & Anxiety
Loss of smell
Sleep disorders
Constipation

ones less common than the above but more frequent than general population:

Dementia
Other psychiatric complications

Question 16

What are pathological hallmarks of Parkinson’s disease?

Answer 16

1.Loss of dopaminergic neurons of the substantia nigra

NORMAL BRAIN SECTION
Neurons visible by eye due to expression of neuromelanin

PARKINSONS DISEASE BRAIN SECTION
Lack of pigmentation shows loss of substantia nigra

2. Histology of dopaminergic neuron loss
3. Proteinopathy again!

Lewy bodies
Intracellular protein aggregates
Enriched in α-synuclein protein

Normal role of α-synuclein is poorly understood (involved in neurotransmitter release)
Lewy bodies not pathogenic, but ↑ α-synuclein is

Question 17

Talk about early onset mitochondrial Parkinson’s Disease(PD)

Answer 17

Mitochondria have a finite lifespan due to oxidative stress
Damaged mitochondria are selectively removed from the cell by “mitophagy” – autophagy of mitochondria
Loss-of-function mutations in two proteins central to activating mitophagy – PINK1 and Parkin – cause EO PD
Mutations in at least 3 other genes linked to mitochondrial stress responses also linked to EO PD
Limitation: this PD is distinct from late-onset sporadic PD (a whole different disease?)

Question 18

Talk about late onset genetic PD

Answer 18

Some genetic causes found from kindred studies (like EO PD), but more limited, including:
SNCA (α-synuclein) gene amplification
Confirms that α-synuclein is pathogenic
LRRK2 gain-of-function
VPS35 gain-of-function
GBA loss-of-function

Question 19

GBA has been linked to alpha-synuclein

Answer 19

GBA encodes GCase (β-glucocerebrosidase ),a lysosomal enzyme
α-synuclein is degraded in the lysosome
They are connected

If less GCA, lysosome is impaired, autophagy is reduced and alpha-synuclein levels increase

if increased a-synuclein, lysosome becomes impaired and then leads to an increase in a-synuclein (pathogenic feed-forward loop!) = increase in alpha-synuclein= decrease in GCase= decrease in lysosomal function

Question 20

Name some other risk factors of Parkinson’s Disease

Answer 20

Gender (more common in men)
Red hair (~2x risk)
Head injury
Not smoking, not consuming caffeine
Herbicides, pesticides, insecticides
Exposure to metals (i.e. welder)
General anaesthesia

Question 21

What is neuroinflammation?

Answer 21

Neuroinflammation = activation of the immune system within the nervous system

Neuroinflammation amplifies the effects of neurodegeneration

Neuronal damage/death—-> neurotoxic insult—–> activates microglial activators (e.g. alpha-synuclein and other proteins)—-> leads to activation of neurotoxic factors which brings back to neuronal damage/death - again another feedback loop

Question 22

What 2 things can microglia be?

Answer 22

Reactive microglia can be protective of neurons or damaging:

Protective
anti-inflammatory, e.g. TGFβ
normal removal of unhealthy cells (i.e. homeostasis)

Damaging
pro-inflammatory, e.g. IL-1, TNF-α
response to pathogens etc(i.e. damage to neurons = ‘collateral damage’)

Aging induces a shift towards production of damaging reactive microglia, due to changes in microglial gene expression (neuroinflammaging)

Question 23

What are some other effects of ageing?

Answer 23

Shortening of telomeres in adult stem cells
Increased reactive oxygen species
Other changes in gene expression
Altered Wnt signalling is a big focus in AD and PD
Wnts are neuroprotective and neuromodulatory
Wnt/β-catenin is decreased in adult brain
Deregulated Wnts in developmental and geriatric neuro conditions?!

Question 24

axon is…

Answer 24

the Achilles heel of a neuron