Neurodegeneration and Alzheimer's disease Flashcards
What is neurodegeneration
progressive loss of function or structure of neurons
What are affected in amyotrophic lateral sclerosis/ motor neuron disease
spinal cord, both lower motor neurons and upper motor neurons are affected, wasting the muscles without innervation
Symptoms in ALS/MND
weakness either in the muscles of limbs or in those used in breathing, swallowing or speech
• More muscles are gradually affected until eventually all voluntary movement is lost and death occurs usually for respiratory failure or lung infections
What is the cause in ALS/MND
10% is inherited mutation in enzyme superoxide dismutase 1 (SOD1)
What will lead to spinocerebellar ataxia and what are the effects
inherited mutation in protein frataxin which lead to neurodegeneration in cerebellum - ataxias
Characteristics of Parkinson’s disease
loss of dopaminergic neuron in the substantia nigra (basal ganglia)
characteristics of Huntington’s disease
it is caused by CAG repeat in huntington protein causing misfolding of protein and death of inhibitory GABAergic neuron in corpus striatum causing uncontrolled unvoluntary movements
How do neurons die
necrotic cell death, apoptosis, autophagy and removing damaged cell can generate further damage
What triggers programmed cell death
cellular stress
Why is it difficult to observe neurodegeneration in vivo
- Cell does not lyse so difficult to observe ongoing apoptosis
- Diseases manifest with clinical signs only when large part of neurons already degenerated and remaining cells are not sufficient to compensate the loss
What is dementia
progressive loss of memory and at least one other cognitive domain, interfering with everyday life
What the five types of dementia
Alzheimer’s, vascular dementia, dementia with lewy bodies, frontotemporal degeneration, and association with PD and HD
What are the symptoms of AD
impairment of declarative memory, memories of remote past are preserved, , cognitive functions decline and eventually lose language completely
Describe the structure of amyloid-B filaments
• flat, pleated domains of different Aβ molecules tend to stick together into aggregates in the shape of fibrils which in turn aggregate in larger, insoluble filaments.
Describe the formation of AB
Ab is derived from amyloid precursor protein (APP)
1. Normally APP is cleaved 2. By enzymes called a- and y-secretases - generating APPsa (trophic and neuroprotective protein) - Non-amyloidogenic processing 3. And two small peptides whose function is unclear 4. APP cleaved by b-secretases (BACE1: beta site-APP cleaving enzyme ) 5. Generating Ab - Amyloidogenic APP processing
Whhat amloid-B exist the most in AD plagues
AB-42, it is more hydrophobic and more prone to aggregate much more easily and more toxic
What is the effect of Amyloid-B
Soluble oligomers are the most toxic form and they impair basic neuronal processes. Imbalance between production and clearance of amyloid B leads to accumulation of toxic protein forming neurofibrillary tangles (NFT) and neuronal dysfunction and death. some also say plagues contribute to alzheimers
How does Tau hypothesis contributes to Alzheimers
- Tau normally binds to microtubules and stabilises them
- Beta amyloid plague initiates pathways that leads to activation of kinase, phosphorylating Tau
- Hyperphosphorylated tau has lower affinity for microtubules and does not bind so well. Microtubules depolymerise.
- Then hyperphosphorylated tau aggregates and forms paired helical filaments and neurofibrillary tangles.
Statements supporting AB hypothesis
- Ab is neurotoxic in vitro
- Ab42 oligomers decrease synapse density and inhibit LTP in rodent hippocampus
- Human Ab42 oligomers induce tau hyperphosphorylation at AD epitopes and cause neuritic abnormalities
- Ab oligomer accumulation appear to precede tau hyperphosphorylation
Statements supporting Tau hypothesis
The severity of AD correlates with the amount of NFTs pathology, not with the amount of plaques
NFTs appear first in the medial temporal lobe and then spreads to the associative cortex, in parallel with neuronal and synaptic loss, while plaques appear first in the cortex, and to a lesser extent in the medial temporal lobe.
Some individuals present a heavy Aβ plaque load at death, but no clinical symptoms
What will Ab plagues cause
- Can disrupts neuron signalling impairing brain function
* Start immune response -> inflammation to destroy surround neurons
* Deposit around blood vessels -> amyloid angiography which weakens the wall of blood vessel and increase the risk of haemorrhage or rupture and blood loss
What is the familial cause of AD
caused by mutation in APP, PSEN-1 or PSEN-1 which are components of y-secretase and can produce more AB-42
What are the five causes of AD
familial cases, down syndrome, ApoE, and other genes
How does Down syndrome contribute to AD
• Gene for APP is on chromosome 21
• Present in three copies in Down’s syndrome
Down’s subjects often present with amyloid plaques
