Neurodegenerative Disorders Flashcards
Name some different types of neurodegenerative disorders
Dementias - Alzheimer’s disease, Fronto temporal dementia and other dementia’s such as lewy body dementia.
Movement disorders such as Parkinson’s disease, Huntington’s disease, motoneurone disease.
Others include spinocerebellar degenerations, spongiform encephalopathies and progressive ms.
What is a neurodegenerative disorder?
Progressive loss of structure and function of neurons including cell death and death of neurons.
What are some epidemiology facts about Alzheimer’s?
Accounts for 70% of all dementia. Predominantly female, mostly sporadic but 10% familial.
Presents with early memory disturbances, progressing to dyspraxia (inability to plan and act out movements), dysphasia and eventually immobile and mute.
What are the signature proteins of Alzheimer’s disease?
Extracellular - Proteinaceous deposits which are largely composed of A beta peptides. (amyloid plaques)
Intracellular fibrils - These are predominantly composed of tau which is a microtubule stabilizing protein. Tau becomes phosphorylated and tangles, it forms paired helical filaments. This effects cellular function
Describe the formation of A beta aggregates
Amyloid precursor peptide (APP) is the precursor for A beta peptides. If APP is cleaved by Beta-secretase then it results if the formation of A beta peptides which are less soluble and aggregate extracellularly to form A beta aggregated which form amyloid fibrils. (toxic for nervous system)
What genes are associated AD sporadic (GWAS) development of alzheimers.
- ApoE4 (effects SORL1 trafficking)
- TREM2 (binds to ApoE and functions in recycling)
- SORL1 (endocytic sorting in retromer)
Thus thought that many of the genes affect endosomal membrane trafficking
Explain the endosomal malfunction that occurs in Alzheimer’s disease
Endosomal enlargement occurs earlier than TAU or amyloid.
When deficient in the sorting complex called retromer, it causes diversion of APP and secretase to the same compartment with production of A beta peptides and causes increase in TAU.
(A retromer defect results in the mixing of Beta-secretase and APP)
What are some methods of detecting Alzheimer’s disease?
- Brain structure using CT/ MRI however this is non-specific.
- Functional PET scan to detect regional cerebral blood flow or cerebral glucose metabolism.
- Amyloid PET scan and Tau PET scan would allow for earlier diagnosis but they are expensive.
- CSF markers
- Peripheral blood markers - pTau 181 assay.
What is the treatment for Alzheimer’s?
- Potential new approach focuses on developing molecular chaperones to improve retromer functions and remove trafficking’s defect. However right now we only have symptomatic treatment:
- Drugs that affect Ach turnover as there is marked loss of Ach due to neuronal loss from nucleus basalis of meynert.
- Drugs that reduce excitotoxity
Name drugs that affect the Ach turnover
- Galantamine
- Donepezil
- Rivastigmine.
They work by acting on N-type receptors or inhibiting acetylcholine easterase.
Used in mild to moderate dementia
Explain the basis behind excitotoxity and a drug used to treat it.
Excitotoxicity refers to neuronal death caused by release of glutamate (release by astrocytes) which acts on extra-synaptic NMDA receptors which drives apoptosis by causing calcium overload.
Memantine is used to treat this as it blocks the current flow by acting as an NMDA receptor antagonist. Used in moderate to severe DAT (dementia of the Alzheimer’s type)
Describe the molecular basis of Parkinson’s disease
Alpha-synuclein accumulation in resulting lewy bodies
Explain the differences between Parkinson’s disease and Lewy body dementia
- Parkinson’s starts with movement disorder and is likely to progress to dementia. Has a genetic predisposition and 10% familial. Has lewy bodies containing alpha-synuclein.
- Lewy body dementia starts with dementia but Parkinson’s can develop. Not usually familial and has different genetic associations. Lewy bodies containing alpha-synuclein.
What are the genes associated with parkinson’s disease
Many of the genes have functions associated with endosomes, for example VPS35 retromer component. Links to alpha-synuclein aggregation.
What are the different types of Motorneurone Diseases?
- Amyotrophic lateral sclerosis (ALS) (UMN and LMN)
- Progressive muscular atrophy (LMN)
- Primary lateral sclerosis (UMN)
- Spinal muscular atrophy
