neurodegenerative diseases

Question 1

define neurodegeneration

Answer 1

neuro and progressive loss

Question 2

basic detail

Answer 2

affect the CNS or PNS

begin at any stage of life

most common are associated with ageing
rarer types of neurodegenerative diseases start in childhood or even from birth
earlier age of onset = greater genetic contribution
later age of onset = more likely a sporadic disease

Question 3

common features

Answer 3

many follow similar pattern:

1. molecular impairment somewhere in cell
2. decreased transmission at synapse
3. cell death

Question 4

common features 2

Answer 4

protein aggregation
lysosomal dysfunction
mitochondrial dysfunction
associated inflammation via activation of glia

Question 5

clinical and research conundrums

Answer 5

neurodegenerative disease rarely manifest overt signs and symptoms until long after neurodegeneration has begun

early treatment is impossible without early diagnosis
therapeutic challenge is considerable

for CNS disorders, studies of affected tissue is very difficult until death

advanced brain pathology is of little help to understanding the causes

neurodegenerative diseases remain incurable

Question 6

alzheimers introduction.

Answer 6

the most common neurodegerative disease and most common cause of dementia

onset is usually >65 years of age, but 10% are early onset, starting 30s onwards

10% people aged 65+
50% people aged 85+

AD is not a normal part of ageing- it is a disease

Question 7

dementia

Answer 7

decline in memory and other cognitive functions that impair quality of life

impairments in dementia are distinct from normal cognitive lapses

Question 8

history of Alzheimer

Answer 8

First described by Alois Alzheimer, a German psychiatrist and neuroanatomist, in 1906/7
Initial psychiatric and pathological observations made in younger patients
“Pre-senile dementia”
Pathology then found to be widespread in older patients

Question 9

pathological hallmarks 2

Answer 9

proteinopathies:

amyloid plaques

• extracellular protein aggregates
• enriched in AB peptides

neurofibrillary tangles

• also called paired helical filaments
• intracellular protein aggregates
• enriched in Tau protein

Question 10

AB and APP

Answer 10

AB peptide is cleaved from a transmembrane protein called amyloid beta precursor protein by proteases

Question 11

amyloid hypothesis

Answer 11

mutations to three proteins involved in AB peptide processing are known to cause rare early onset form of Alzheimers

APP
PSEN1
PSEN2

since early 1990s amyloid hypothesis of AD which states AB and or amyloid plaques are cause of AD

Question 12

TAU and neurofibrillary tangles

Answer 12

tau normally binds microtubules in axons

hyperphosphorylated tau is displaced causing:

• tangles
• destabilised microtubules

Question 13

importance of microtubules in neurites

Answer 13

in all post mitotic cells, microtubules have 3 main roles:

1. structure/shape of cell
2. positioning of organelles
3. motorways for transporting vesicular cargo

Question 14

tau hypothesis

Answer 14

in typical late onset AD

neurofibrillary tangles are:

• seen before amyloid plaques
• well correlated with cell death and progression

-suggests Tau is upstream AB = tau hypothesis

Question 15

tau or amyloid

Answer 15

still really controversial

probably more evidence for amyloid, but therapies based on inhibiting AB aggregation so far haven’t worked

tangles and plaques may be red herrings
- oligomeric forms of AB and tau are more likely to be pathogenic

Question 16

other risk factors

Answer 16

Down syndrome
gender
high BP, cardiovascular disease, diabetes

low education
head injury

smoking and drinking

only small genetic risk contribution for late-onset AD

Question 17

parkinsons introduction

Answer 17

second most common neurodegenerative disease

onset usually 60-65 years of age, 10% start before 45 years of age

lifetime risk:

• male = 2%
• female = 1.3%

like AD, Parkinson’s is incurable

Question 18

symptoms of Parkinson’s

Answer 18

movement disorder, with four cardinal features

1. resting tremor
2. bradykinesia
3. rigidity
4. postural instability

Question 19

non-motor symptoms

Answer 19

• 90% of patients display additional non-motor symptoms

including:

• depression
• loss of smell
• sleep disorders
• constipation
• dementia
• other psychiatric complications

Question 20

pathological hallmarks 1

Answer 20

loss of dopaminergic neurons of substantial nigra

• neurons that produce the neurotransmitter dopamine
• part of basal ganglia in midbrain substatia nigra = dark substance

normal brain section:
- neurons visible by eye due to expression of neuromelanin

PD brain section = lack of pigmentation shows loss substantially nigra

Question 21

pathological hallmarks 1

Answer 21

histology of dopaminergic neurone loss

Question 22

pathological hallmarks 2

Answer 22

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 23

familial PD

Answer 23

10% of cases have clear genetic cause

three rough categories:

1. early/juvenille onset recessive mitochondrial conditions
2. late/later onset autosomal dominant PD
3. mutations that cause PD plus conditions

Question 24

early onset mitochondrial PD

Answer 24

mitochondria have finite lifespan due to oxidative stress

damaged mitochondria are selectively removed from 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 is PD distinct from late-onset sporadic PD

Question 25

late onset genetic PD

Answer 25

• some genetic causes found from kindred studies, but more limited:
• SNCA gene amplification
• LRRK2 gain of function
• VPS35 gain of function
• GBA loss of function

Question 26

GBA and a-synuclein

Answer 26

GBA encodes GCcase B glucocerebrosidase

a-synucelin is degraded in the lysosome

they are connected

Question 27

PD and lysosomes

Answer 27

other PD genes play roles in processes involving lysosomes

consistently, autophagy is dysregulated in PD brains

problems in autophagy will also lead to mitochondrial dysfunction

endocytic pathways are big focus in PD research

Question 28

GWAS of sporadic PD

Answer 28

risk genes:

• has shown many cause genes influence risk
• found many new PD genes
• now believed as much as 30% of PD risk is genetic

Question 29

Tau and PD

Answer 29

linkage of MAPT to PD was a big surprise

neurofibrillary tangles can be found in PD brain, but not to any great extent

however,
more NFTs in brains of LRRK2 PD
microtubule disruption long implicated in PD

Question 30

other risk factors

Answer 30

gender
red hair 
head injury 
not smoking, not consuming caffeine 
herbicides, pesticides, insecticides
exposure to metals 
general anaesthesia

Question 31

neuroinflammation

Answer 31

activation of the immune system within the nervous system

in brain, typically means activation of microglia

Question 32

ageing and microglia

Answer 32

reactive microglia can be protective of neurons or damaging

protective = anti-inflammatory, normal removal of unhealthy cells

damaging;
= pro inflammatory, response to pathogens

ageing induces shift towards production of damaging reactive microglia, due to changes in microglial gene of expression

Question 33

neuroinflammation in neurodegeneration

Answer 33

external trigger = AB, environmental toxins, pathogens

microglial activators= a-synuclein and other proteins

neurotoxic insult = injury, toxins, gene, mutations

neuronal damage/death

Question 34

neuroinflammation as a cause

Answer 34

Many Alzheimer’s risk factors cause raised levels of circulating inflammatory cytokines
High BP, Cardiovascular disease, Diabetes, Smoking
In principal, effects can cross the blood-brain barrier
Enough to cause AD? Not known
But an interesting story emerging in PD…

Question 35

PD gut-to-brain

Answer 35

Lewy body pathology in gut often precedes pathology in brain
Evidence that gut inflammation is sufficient to cause gut Lewy bodies
Spread to brain via vagus nerve?
Role for microbiota?

Question 36

other effects of ageing

Answer 36

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?!