Alzeihemers Flashcards
popular neurodegenerative diseases (NDD)
Alzeiheimer
Dementia
Parkinson’s
motor neuron disease
Huntington disease
NDD based on anatomic structure
-Frontotemporal dementia
-Extrapyramidal disorder
-Spinocerebella ataxia
-Spinal muscular atrophy
Principle molecular abnormality in NDD
Dysregulation of synuclein
Amyloid processing
NDD causes
Combination of genetic and environmental factors
-greatest risk factor is age
-Inherited disorders
-long term exposure to pesticides, toxins and chemicals have been linked to parkinsons
Main problem of NDD
-Not curable
-Leads to problems in movement (ataxia), mental functioning (dementia) and affect a person’s ability to move, speak and breath
Alzeihemers (AD) demographic
60-70% of all dementia cases
one in every 68 individuals
SA= 850 000 cases
Parkinsons demographic
1 in 5000-10,000
Huntington disease demograph
1 in 10,000-20,000
Summary of neurodegenerative diseases
Insert
AD definition
It is characterised by the presence of extracellular amyloid plaques and intracellular neurofibrillary tangles, resulting in neuronal dysfunction and apoptosis
APP
Amyloid precursor protein
Normal treatment of APP
APP undergoes proteolytic processiing, cleaved by alpha-secretase to generate soluble peptide sAPP(alpha=a) and a C83 carboxy-terminal fragment resulting in an integral membrane protein that is activated
-APP is inactive
function of sAPPa
-Associated with normal synaptic signalling
-Regulates processes like neuronal survival and synaptic platicity that contribute to higher-order brain functions like learning, memory and other behaviours
Problem with APP processing
Mutations lead to formation of B-secretase and gamma-secretase which cleave APP to release extracellular monomers of varying sizes, the most signifcant Amyloid Beta-peptide 1-40/42 (ABeta40/42)
Effects of Abeta
-The APP imbalance increases neurotoxic aggregation, yielding Abeta oligomerisation and plaque formation
-ABeta aggregation leads to blocked ion channels, disruption of calcum homeostasis and mitochondrial oxidative stress
-Impaired energy metabolism and abnormal glucose processing
-Alters synaptic functioning which leads to cell death
cells affected by Ab
Glial cell types like astrocytes and microglia are affected
-Glial cells play an NB role to protect neuronal environment
Overall effect of Ab
accumulation of amyloid monomers, oligomers and plaque affects neuronal and glial cells which results in vulnerable neurons and cell death
Neurofibrillary tangles
-Composed of hyperphosphorylated forms of microtubule-associated protein Tau
Phosphorylation of Tau
Primary kinases responsible for phosphorylation are GSK-3a/B and CDK5
-Other kinases such as PKC, PKA and Erk2 are also involved
Effect of phosphorylated Tau
-Hyperphosphorylation leads to the dissociation of Tau from the microtubule which is followed by microtubule destabilisation and oligomerisation which forms neurofibrillary tangles
-Accumulation of tangles leads to neuron apoptosis
Mental health status testing
Doctors perform thinking (cognitive) and memory skills tests
-These scores are used to evaluate degree of cognitive impairment
Neuropsychological tests
-Conducted by a specialist trained in brain conditions and mental health conditions (neuropsychologist)
-Evaluation can include extensive tests to evaluate memory and thinking (cognitive) skills
Laboratory tests
-Measure accumulation of amyloid and tau proteins from cerebrospinal fluid
-ratio of these proteins can help determine alzeihmers presence
-Most cases, cerebrospinal fluid test is unnecessary and is only useful in atypical or rapidly progressive cases
AD treatment
-No cure
-Best way to treat is through palliative care (reduce symptoms but not cure or change disease)
-Some medications can potentially slow down AD but not to a significant extent
AD medication
Acetylcholine esterase inhibitor like Rivastigmine
AD summary
Dysregulation of processing of Ab in phosphorylated Tau leads to formation of plaques and development of AD
-Enzymes such as a-secretase has a crucial role in pathogenesis of AD
