neurodegenerative diseases Flashcards
What are neurodegenerative disorders?
- gradual dysfunction of neurons over time eventually leading to death of neurons
- usually progressive dysfunction
What is dementia?
- significant loss of intellectual abilities including cognition, memory capacity, concentration & judgement
- can be severe enough to interfere with social or occupational function
- gets progressively worse over time
What anatomical changes happen to the brain during alzeimers disease?
- severe cortical shrinkage
- severly enlarged ventricles
- severe shrinkage of hippocampus
what is the leading cause of dementia?
Alzheimer’s disease - a neurodegenerative disorder
What are the main 2 hallmarks of Alzheimer’s disease?
- amyloid plaques
- neurofibrillary tangles
What are amyloid beta plaques?
- extracellular deposits of the amyloid beta protein
What are neurofibrillary tangles?
- insoluble fibers found in neurons
- consist of an abnormally phosphorylated protein called Tau
- note that tau is important for microtuble transport
- therefore the disease causes the microtubule within the neurons collapse and cause cell death
What are neurofibrillary tangles associated with?
- loss of neurons and synapses, brain atrophy ( wastage) & ventricle enlargement
Discuss the role of Tau with microtubules- what are mt’s.. how does tau bind and what happens with disorders
- microtubules represent tracks for fast axonal distribution of cellular organelles
- Tau binds and stabilizes the mt’s
- dephosphorylation by phosphatase enzymes strengthens the affinity of Tau for microtubules
- phosphorylation of certian enzymes inhibit the binding of tau to microtubules which leads to depolymerisation of them
- UNBOUND, ABNORMALLY PHOSPHORYLATED Tau aggregates into paired filaments
What is alpha beta?
- fragment of a larger protein called the amyloid precursor protein APP
What is APP? - also mention its role in AD
- membrane bound protein which is expressed under normal conditions and is involved in neural growth and repair
- cleavage of APP in AD which causes pathophysiological accumulation - forms hard insoluble plaques between nerve cells
What is the cleavage of APP mediated by?
- mediated by a family of enzymes called secretase enzymes
Describe the non amyloidogenic pathway of cleaving APP
- alpha secretase cleaves within the APP fragment to produce APPsa
- gamma secretase cleaves APPsa to produce p3 fragment P3 fragments can be found in amyloid plaques
Describe the amyloidogenic pathway in APP cleavage
- step 1: beta secretase cleaves APP at the amino terminus of the alpha- beta peptide . This releases APP-s beta
- step 2: gamma secretase cleaves APPs Beta to produce the full length alpha beta peptide
- alpha beta fragments aggregate extracellularly to cause plaques
What is familial Alzheimer’s disease?
- genetic component
- often associated with mutations in the APP gene or mutations in the enzymatic components of the secretase family of proteins
- autosomal dominant inheritance
-rare
What is sporadic Alzheimer’s disease?
- cause is still unknown
- 90% of cases
- age is largest risk factor - 65 and older
- other risk factors : history of traumatic injury to the brain
How can Alzheimer’s be treated? 1 way
- acetylcholinesterase inhibitors
- loss of cholinergic transmission and Ach synthesizing neurons in subcortical nuclei of the forebrain
- improves cognition, behavior and functional ability BUT only in apporx 20% of patients
How can AD be treated ? way 2
- NMDA receptor antagonists / partial antagonists
- these address the problem of inappropriate glutamate/NMDA receptor over activation
what are mild symptoms in Alzheimer’s disease?
-confusion and memory loss
-personality changes
-judgement problems
difficulty w/ routine tasks
what are examples of moderate symptoms associated with Alzheimer’s disease?
-difficulty w/ personal care eg bathing and dressing
-anxiety
-insomnia or sleep disturbances
-wandering and pacing
-trouble with recognising familiar faces
what are examples of severe symptoms associated with Alzheimer’s disease?
-loss of speech
-loss of appetite
-loss of bladder and bowel control
-complete dependence on caregiver
what is cretutzfeld jakobs disease?
- a prion disease
- an abnormal protein In the brain triggers the folding of normal proteins in the brain
-untreatable and fatal
what are examples of symptoms of CJD?
- loss of memory
-mood changes
-clumsiness
-jerky movements
what are the 3 different types of CJD?
-acquired
-sporadic CJD - cause unknown - affects adults > 50 yrs
-variant CJD - new type - affects young people
what is hungtinton’s disease?
-hereditary neurodegenerative disorder
-caused by a mutation in the HPP gene which leads to the abnormal production of the hungtinton protein
-degeneration of GABAergic neurons In striatum
