Neurological disorders Flashcards
what is meant by a neurons “achilles heel”
distance between axons terminal and nucleus
what is dementia
a decline in memory and other cognitive functions that impair quality of life
what are the pathological hallmarks of Alzheimer’s
- Brain shrinkage ( shrinkage of cerebral cortex and hippocampus)
- Proteinopathies
Proteinopathies in Alzheimer’s
- amyloid plaque
- -Extracellular protein aggregation
- -enriched in Abeta peptides
- Neurofibrillary tangles
- also called paired helical filaments
- -intracellular protein aggregates
- -enriched Tau protein
Abeta and APP
Abeta peptide is cleaved from a
transmembrane protein called amyloid
beta precursor protein (APP) by proteases
AMYLOID HYPOTHESIS
• Mutations to three proteins involved in Abeta peptide processing
are known to cause rare early onset forms of Alzheimer’s
— APP
— PSENI
— PSEN2
Presenilin-l and PreseniIin-2;
both a components of y-secretase
TAU AND
NEUROFIBRILLARY TANGLES
• Tau normally binds microtubules in axons •Hyperphosphorylated tau is displaced causing: — Tangles — Destabilised microtubules
Other risk factor of Alzheimer’s
- Down syndrome (APP is on chromosome 21 )
- Gender (more common in women)
- High BP, Cardiovascular disease, Diabetes
- Low education
- Head injury
- Smoking and drinking
Symptoms of parkinsons disease
resting tremor, bradykinesia, rigidity,postural instability
Non motor symptoms of Parkinson’s (4 pts)
-depression and anxiety
-loss of smell
-sleep disorders
-constipation
less common( dementia and other psychiatric complication )
Pathological hallmarks of Parkinson’s
- loss of dopaminergic neurons of the substantia nigra
- proteinopathies
proteinopathies of Parkinson’s
Lewy bodies — Intracellular protein aggregates — Enriched in a-synuclein protein Normal role of a-synuclein is poorly understood (involved in neurotransmitter release) • Lewy bodies not pathogenic, but increased a-synuclein is
EARLY ONSET
MITOCHONDRIAL PD
- 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 — PINKI and Parkin — cause EO PD
LATE ONSET GENETIC PD
Some genetic causes found from kindred studies (like EO
PD), but more limited, including:
-SNCA (a-synuclein) gene amplification
• Confirms that a-synuclein is pathogenic
-LRRK2 gain-of-function
-VPS35 gain-of-function
-GBA loss-of-function
GBA & a-SYNUCLEIN
-GBA encodes GCase (ß-glucocerebrosidase),
a lysosomal enzyme
-a-synuclein is degraded in the lysosome
pathogenic feed-forward loop (GBA &a-SYNUCLEIN)
increased a-synuclein inhibits GCase which reduces Lysosomal function which increases a-synuclein and the cycle repeats
Tau AND PD
-Neurofibrillary tangles can be found in PD brains (even in same cells as Lewy bodies), but not to any great extent -More NFTs in brains of LRRK2 PD -Microtubule disruption long implicated in PD
Other risk factors in Parkinson’s
- Gender (more common in men)
- Red hair risk)
- Head injury
- Not smoking, not consuming caffeine
- Herbicides, pesticides, insecticides
- Exposure to metals (i.e. welder)
- General anaesthesia
What is neuroinflammation
activation of the immune system within the nervous system
In the brain this is done by activation of microglia
what is reactive microglia
- amoeboid shape
- more motile
- production of cytokines
- eventually phagacytotic
Neuroinflammation in neurodegeneration
activation of
‘reactive’ microglia causes release of IL-1B , TNF-a, prostaglandin( neurotoxic factors)
This causes neuronal damage/death along with neurotoxic insult like injury, toxins, gene mutation. This results in activation of microglia via microglia activators like a-synuclein and other proteins. This cycle is then repeated
Protective features of microglia
-anti inflammatory, e.g. TGFß
-normal removal of unhealthy cells (i.e. homeostasis)
• Damaging
Damaging features of microglia
— pro-inflammatory, e.g. IL-I , TNF-a
— response to pathogens etc
(i.e. damage to neurons = ‘collateral damage’)
what is neuroinflammaging
Aging induces a shift towards production of damaging reactive
microglia, due to changes in microglial gene expression
effects of ageing
• 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/ß-catenin is decreased in adult brain
