Ageing and Neurodegeneration

Question 1

What is Huntingdon’s disease?

Answer 1

• Autosomal Dominant Inheritance
• changes to structures of brain
• can inherit a defective copy of the gene from the Dad

Question 2

What is the pathology of Huntingdon’s disease?

Answer 2

• exact function of normal Huntingtin protein is poorly defined
• Acuumulation of the abnormal protein - may cause neurological changes
  Excess of the mutated protein interfers with neurotransmiters

Question 3

What are the pathological protein changes that occur in HD?

Answer 3

• Expansion of DNA repeat region
• Translates to an unstable poly-glutmine repeat in the protein product
  Repeats in excess of 40 are considered to be pathological
  Expanded poly-glutamine region of the patholgical form of the protein causes impairment of the ubiquitin-proteasome system
• Dysfunctional protein is not removed and destroyed as it should be

Question 4

What are the symptoms of HD?

Answer 4

• • Cognitive
• Muscular abnormalities
  -Behavioural : compulsive behaviour etc
• Psychological; delirium, depression , hallucination or paranoia
• Mood ;anxiety, apathy , mood swings
• Tremors, weight loss or impaired voice

Question 5

What is the physiology of the ageing central nervous system?

Answer 5

• Cell loss : Brain weight increases to age 30, declines by 10% by 90 yrs old
• Causes ventricles to enlarge
  -Gyri become smaller, sulci between them enlarge
• Grey and white matter reduced

Question 6

What happens to the CNS in ageing?

Answer 6

• Neuronal function declines : rate of conduction alongaxons declines, due to loss of myelin
• Synapses time increases
  Reducued levels of synapse enzymes, receptors
• Reduced numbers of dendrites and dendritic spines (in some areas of the brain)
  -Lipofuscin deposits
  Decrease in dark staining cytoplasmic Nissl bodies
• Glia : 10X more glail cells then neurons, decrease/increase in some areas

Question 7

What are the forms of dementia?

Answer 7

• Alzheimer’s
• Vascular dementia
• Lewy body dementia
• Frontotemporal dementia

Question 8

What is Alzheimer’s Disease?

Answer 8

• Neurodegenerative disease causing progressive memory and language loss
• Associated with deposition fo amyloid protein (APP) in CNS and neurofibrillary tangles (NFTs)
• NFTS associated with mutations to Tau proteins that stabilise microtubules
  Mutations to PS-1and 2 (presenelin genes) give rise to early onset disease
• Mutation to apoliporoprotein E gives rise to late onset

Question 9

What is Amyloid precursor protein?

Answer 9

• A membrane protein that sits in the membrane and extends outward
  -Important for neuronal growthm survival and repair
• Enzymes cut the APP into fragments, most important of which for AD = B-amyloid
  BA = sticky , so fragments cling together along with other material outside of the cell, which forms plaques seen in the AD brain

Question 10

What is the pathogenesis of AD?

Answer 10

• Rate of beta amyloid accumulation and aggregation determined by :
  -Genotype, production of amyloid peptide, tau , presenilin proteins
  -Efficiency of degradation
• Levels of plasmin (cleavage product of plasminogen)

Question 11

What is Parkinson’s Disease?

Answer 11

• progressive neurodegenerative disease
• Inciidence : 1 in 200 over the age of 55

Question 11

What is the amyloid hypothesis?

Answer 11

• Trigger for AD is the A-beta peptide and the accumulation of this peptide in the form of plaques iis the initiating molecular event
  Plaques trigger an inflammatory respons, evoke neuronal cell death and gradual cognitive decline

Question 12

What are the clinical descriptions of PD?

Answer 12

• Useless contractions of the skeletal muscles causing muscle rigidity and tremors
  -Resting tremor, muscular rigidity, bradykinesia and postural instability
• 20% of patients develop Alzheimer’s disease

Question 13

What are the pathological features of PD?

Answer 13

• Loss of dopaminergic neurons in the substantia nigra
• Presence of Lewy bodies (clumps of alpha-synuclein), intracellular inclusions in surviving neurons in various areas of the brain , particularyly SN
• Leads to reduced production of dopamine
• Reduced dopamine levels leads to striatral dopamine deficiency and development of PD symptoms

Question 14

What is the role of dopamine?

Answer 14

• Acts to oppose acetylcholine (excitatory)
• Dopamine inhibitatory
• Depletion in dopamine reuslts in hypokinetic disorders such as PD
• May also lead to dementia by Lewy bodies using up acetylcholine (Lewy body dementia

Question 15

What is Lewy body disease?

Answer 15

Mutations in Alpha-synuclein can lead to either mendelian Parkinsons or Lewy body dementia
- Triplication of Alpha -synuclein leads to disease onset in the 30s
- Normal genetic variability : people with highr expressing alleles have a higer risk of sporadic disease