neurodegenerative diseases

Question 1

what is a neurodegenerative disease

Answer 1

the loss of neurons 
affect CNS/PNS or both 
begin at any stage of life
earlier onset = greater genetic contribution 
highly heterogenous

Question 2

features of neurodegenerative disease

Answer 2

molecular impairment somewhere in cell
decreased transmission at synapse
cell death

Question 3

define Achilles heel

Answer 3

distance between axon terminal and nucleus

Question 4

describe alzheimers

Answer 4

most common and common cause of dementia
onset usually >65 years
10% nearly onset
not normal part of ageing
shrinkage in brain/hippocampus
proteinopathies = amyloid plaques and neurofibrically tangles

Question 5

define dementia

Answer 5

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

Question 6

what are amyloid plaques

Answer 6

extracellular protein aggregates

enriched in AB peptides

Question 7

what are neurofibrillary tangles

Answer 7

called paired helical filaments
intracellular protein aggregates
enriched in Tau proteins

Question 8

what are common causes of Alzheimers

Answer 8

AB = peptide cleaved from transmembrane protein called amyloid beta precursor protein (APP) by proteases

Question 9

what is the amyloid hypothesis

Answer 9

mutations to 3 proteins involved in AB peptide processing which cause rare early onset alzheimers

Question 10

tau and neurofibrillary tangles

Answer 10

tau normally binds microtubules in axons

hyperphosphorylated tau is displaced causing: tangles and destabilised microtubules

Question 11

describe importance of microtubules in neurites

Answer 11

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

Question 12

describe tau hypothesis

Answer 12

in late onset alzheimers, neurofibrillary tangles are:

• seen before amyloid plaques
• well correlated with cell death and progression
• suggests tau is upstream AB

Question 13

risk factors for ND

Answer 13

Down syndrome 
gender (more common in women)
high BP, cardiovascular disease
low education 
head injury 
smoking and drinking

Question 14

Parkinsons disease

Answer 14

2nd most common

symptoms:

• resting tremor
• bradykinesa
• rigidity
• postural instability

Question 15

non-motor symptoms of Parkinson’s

Answer 15

depression or anxiety
loss of smell 
sleep disorders 
constipation 
dementia 
other psychotic complications

Question 16

pathological hallmarks

Answer 16

loss of dopaminergic neurons of substantial nigra and others = dark substance

Question 17

what is proteinopathy

Answer 17

Lewy bodies
= intracellular protein aggregates enriched in alpha-synnuclein protein

alpha synnuclein = involved in neurotransmitter release

Lewy bodies not pathogenic but increased alpha synuclein is

Question 18

causes of parkinson’s

Answer 18

10% genetic cause
mutations = later onset
recessive mitochondrial conditions = early/juvenille

Question 19

early onset mitochondrial PD

Answer 19

damaged mitochondria selectively removed from cell by mitrophagy = auto-Phagy of mitochondrial

loss of function in 2 proteins central to activating mitopahgy = PINK1 and Parkin

Question 20

describe late onset PD

Answer 20

mutation is a-synuclein gene amplification
LRRK2 gain of function
VPS35 gain of function
GBA loss of function

Question 21

describe GBA and a-synuclein

Answer 21

GBA encodes Case, a lysosomal enzyme
a-synuclein is degraded in the lysosome
both are connected

increased a-synuclein = decreased GCase = decreased lysosomal function

Question 22

PD and lysosomes

Answer 22

autophagy is dysregulated in PD brains

problems in autophagy leads to mitochondrial dysfunction

Question 23

describe risks of PD

Answer 23

risk genes = 30% risk contribute to PD

Question 24

tau and PD

Answer 24

can be found in PD brains, but not many
more NFTs in brains of LRRK2 pD 
microtubule disruption long implicated in PD
Gender = more common in men
red hair = x2 risk 
heady injury 
not smoking = not consuming caffeine 
herbicides, pesticides and insecticides 
exposure to metals 
general anaesthesia

Question 25

describe neuroinflammation

Answer 25

activation of the immune system within the nervous system

in brain = activation of microglia > activated = amoeboid shape more motile produces cilia phagocytic

Question 26

describe neuroinflammation in neurodegeneration

Answer 26

1. neurotoxic insult = causes neuronal damage/death
2. activates microglial activators
3. neurotoxic factors produced = IL-1B TNF-a

Question 27

describe ageing and microglia

Answer 27

reactive microglia = protective/damaging of neurons

protective = anti-inflammatory or normal removal of unhealthy cells

damaging = pro-inflammatory/response to pathogens

ageing induces shift towards production of damaging forms of microglia

Question 28

PD gut > brain

Answer 28

Lewy body pathology in gut precedes pathology in brain

gut inflammation - gut Lewy bodies

Question 29

effects of ageing on neurodegeneration

Answer 29

shortening of telomeres in adult stem cells
increased reactive oxygen species
other changes in gene expression