Neurodegenerative Diseases Flashcards
Define neurodegenration
neuro (relating to neurons) + degeneration (progressive loss)
What is a neurodegenerative disease
any disease caused by neurodegeneration
What are some features of neurodegenerative diseases
Affect the CNS or PNS (or both)
Begin at any stage of life:
- The most common ones are associated with ageing
- Rarer types of neurodegenerative disease start in childhood or even from birth
- Earlier age of onset = greater genetic contribution
- Later age of onset = more likely a sporadic (or idiopathic) disease
Why are neurodegenerative diseases highly heterogeneous
- Some disease names are really umbrella terms. Conditions with overlapping phenotypes, but distinct causes (e.g. at least 25 types of SCA from mutations in different genes)
- Some diseases are inherently pleiotropic symptoms manifest differently in different people e.g. Parkinson’s disease symptoms unique to individual)
what are some common features of AD?
Many follow a similar pattern:
- Molecular impairment somewhere in the cell
- Decreased transmission at synapse
- “Dying back” of neurites (axons and/or dendrites)
- Cell death
Frequently involve:
- Protein aggregation (“proteinopathies”)
- Lysosomal dysfunction
- Mitochondrial dysfunction
- Associated inflammation via activation of glia
What are the clinical and research challenges
- Neurodegenerative diseases rarely manifest overt signs and symptoms until long after neurodegeneration has begun
Early treatment is impossible without early diagnosis
The therapeutic challenge is considerable
- For CNS disorders, studies of affected tissue is very difficult until death
Advanced brain pathology is of little help to understanding the causes - Neurodegenerative diseases remain incurable
What is Alzheimer’s disease
- The most common neurodegenerative disease and the most common cause of dementia
- Onset is usually >65 years of age, but ~10% are “early onset” starting ~30s onwards
- Incidence:
10% of people aged 65+
50% of people aged 85+ - AND is NOT a normal part of ageing, it is a disease
What is dementia
- A decline in memory and other cognitive functions that impair quality of life
- Impairments in dementia are distinct from “normal” cognitive lapses
How was Alzheimers discovered
- First described by Alois Alzheimer, a German psychiatrist and neuroanatomist, in 1906/7
- Initial psychiatric and pathological observations made in younger patients
“Pre-senile dementia” - Pathology then found to be widespread in older patients
What is the 1st pathological hallmark of Alzheimer’s
Brain shrinkage
What is the 2nd pathological hallmark of Alzheimer’s
Proteinopathies:
- Amyloid plaques
Extracellular protein aggregates
Enriched in Aβ peptides - Neurofibrillary tangles
Also called paired helical filaments
Intracellular protein aggregates
Enriched in Tau protein
Describe Amyloid plaque formation
Aβ peptide is cleaved from a transmembrane protein called amyloid beta precursor protein (APP) by proteases:
- B-secretase
- Y-secretase
what is the amyloid hypothesis?
- Mutations to three proteins involved in Aβ peptide processing are known to cause rare early-onset forms of Alzheimer’s
APP
PSEN1
PSEN2
PSEN1/2 both are components of y-secretase
- Since early 1990’s “Amyloid hypothesis of AD”, which states that Aβ and/or amyloid plaques are the cause of AD
Explain tau and the formation of neurofibrillary tangles
- Tau normally binds microtubules in axons
- Hyperphosphorylated tau is displaced causing:
Tangles
Destabilised microtubules
what is the importance of microtubules in neurites
In all post-mitotic cells, microtubules have 3 main roles:
- Structure/shape of cell
- Positioning of organelles
- Motorways for transporting vesicular cargo
What is the Tau hypothesis
- In typical late onset AD (i.e. not genetic forms of AD), neurofibrillary tangles are:
Seen before amyloid plaques
Well correlated with cell death and progression - Suggests Tau is upstream Aβ = Tau hypothesis