42. Degenerative Disease Due To Amyloid Flashcards
What are some examples of chronic degenerative disorders?
- Alzheimer’s Disease
- Parkinson’s Disease
- Huntington’s Disease
- Type II diabetes
- Senile heart failure
Describe the population impact and demographics of chronic degenerative diseases.
- They are under-recognised in terms of their effect on long-term morbidity and mortality
- The number of cases each year is increasing due to:
- Better diagnosis
- Ageing population
Chronic degenerative diseases are diseases of…
Ageing
What is amyloid?
*Fibrillar deposits of abnormally folded host protein that provoke degenerative reactions.
* Amyloid is usually protease-resistant, fibrillar and dominated by beta-sheet
What do amyloid diseases differ in?
Amyloid diseases differ in:
- Identity of the protein involved
- Site of deposition
- Pathological consequences
- Causative or risk factors
What are the pathological consequences of amyloid diseases?
- The specific protein affected determines which tissues will be affected
- The damage directly or indirectly (via inflammation) leads to cell loss and loss of function
- Chronic inflammation is increasingly implicated as a source of damage in these diseases
What are amyloid diseases?
- They are diseases characterised by fibrous deposition of amyloid within cells, leading to their dysfunction and provoking degenerative reactions
- They include diseases such as Alzheimer’s disease
Summarise the formation of amyloid.
- Normal host proteins are misfolded -> This often involves a change from alpha helix-rich to beta sheet-rich proteins
- These misfolded protein accumulate first in oligomers, then protofibrils and finally 7-10nm fibrils
- They are resistance to proteases, so they build up
What are some possible causes of amyloid diseases?
- Infectious -> Pathogen’s abnormal protein causes a change in the host cell protein (e.g. vCJD)
- Genetic -> Inherited propensity for a protein to misfold (e.g. FFI)
- Chronic disease -> Leads to excess production of serum proteins, which can be misfolded
- Ageing -> Failure of normal clearance mechanisms)
What protein do amyloid disorders involve?
They all affect a specific protein (not the same one).
What are the peripheral amyloid disorders you need to know about?
- Alzheimer’s disease (senile dementia)
- Parkinson’s disease
- Secondary (peripheral) amyloidoses in chronic inflammatory diseases
- Type II diabetes
- vCJD
What is secondary amyloidosis?
Secondary or AA amyloidosis occurs when serum amyloid A protein — an acute phase reactant produced in response to a variety of infectious, inflammatory, or neoplastic insults — accumulates in the kidneys, gastrointestinal tract, and heart. It has been associated with conditions as diverse as familial Mediterranean fever, rheumatoid arthritis, ankylosing spondylitis, severe gout, tuberculosis, bronchiectasis, osteomyelitis, inflammatory bowel disease, Hodgkin’s disease, and renal-cell carcinoma. Treatment is directed at the underlying disease process.
For secondary amyloid disease, state:
- Abnormal protein
- Cause
- Pathology
- Abnormal protein -> Serum amyloid A precursor protein
- Cause -> Chronic inflammation
- Pathology -> Heart and kidney
Where globally are secondary (peripheral) amyloidoses in chronic inflammatory diseases most commonly seen?
In developing countries.
For type II diabetes as an amyloid disease, state:
- Abnormal protein
- Cause
- Pathology
- Abnormal protein -> 37-mer Islet amyloid precursor polypeptide
- Cause -> Chronic inflammation
- Pathology -> Pancreatic islet dysfunction
What contributes to DMT2?
Multifactorial, especially obesity.
Which system is particularly prone to amyloid diseases?
CNS
What are some amyloid diseases of the CNS?
- Alzheimer’s disease
- Parkinson’s disease
- vCJD
For Alzheimer’s disease, state:
- Abnormal protein
- Part of the CNS affected
- Abnormal protein -> Amyloid β A4 precursor protein (APP) or Presenilin 1 or 2 [EXTRA]
- Part affected -> Cortex
For Parkinson’s disease, state:
- Abnormal protein
- Part of the CNS affected
- Abnormal protein -> α-Synuclein
- Part affected -> loss of dopaminergic neurons in basal ganglia
What is the rate model for PD?
Rate model → loss of nigrostriatal dopamine input → over-activity of inhibitory indirect pathway in hypokinesia. HOWEVER
*Does not explain key finding that lesions of motor thalamus or GPe do not result in bradykinesia or akinesia
*Does not explain finding that GPi lesions in PD patients do not result in dyskinesias
What is the new model for PD?
Replacement model/ current favour model: PD due to disruption of normal cortico circuits because of presence of abnormal firing patterns + abnormal synchronisation → excessive beta-band oscillations & reduction in gamma-band oscillations in the motor circuit.
gWhat are Lewy Bodies?
Insoluble IC protein aggregates associated with PD
*largely composed of α-synuclein
*misfolding/ phosphorylation of α-synuclein → formation of aggregates analogous to amyloid plaques in AD.
*Progressing from oligomers → protofibrils → large insoluble fibrils.
What is CJD?
Creutzveldt-Jakob disease
For Creutzveldt-Jakob disease, state:
- Abnormal protein
- Cause
- Abnormal protein -> PrP (prion protein)
- Cause -> Spontaneous
For vCJD, state:
- Abnormal protein
- Cause
- Abnormal protein -> PrP (prion protein)
- Cause -> Infectious
What are some diseases caused by prions?
- Creutzveldt-Jakob disease
- vCJD
- Fatal familial insomnia
What are prions and how do they relate to amyloids?
- Prions are misfolded proteins with the ability to transmit their misfolded shape onto normal variants of the same protein.
- They characterize several fatal and transmissible neurodegenerative diseases.
- Prions are a subclass of amyloids in which protein aggregation becomes self-perpetuating and infectious.
What are prion diseases and what are they caused by?
- A family of chronic neurodegenerative diseases characterised by extensive neuronal loss without replacement by glial cells, leaving large vacuolated areas clearly seen in histological sections
- They are often fatal
- Causes: Sporadic, genetic predisposition or infectious
What are the features of prion diseases?
- Progressive
- Irreversible
- Fatal
- Vacuolating neurodegeneration
- Often amyloid plaques
- Often diffuse and/or focal accumulations of proteaseresistant PrP
- Infectivity associated with abnormal PrP, no DNA
What enables the infectivity of prion diseases?
The abnormal prion protein (PrP) itself conveys infectivity, not any DNA.
What are the symptoms of Creutzveldt-Jakob disease?
- Rapidly developing delirium or dementia (over the course of a few weeks or months)
- Blurred vision (sometimes)
- Changes in gait
- Hallucinations
- Lack of coordination (for example, stumbling and falling)
- Muscle twitching
- Muscle stiffness
- Myoclonic jerks or seizures
- Nervous, jumpy feelings
- Personality changes
- Profound confusion, disorientation
- Sleepiness
- Speech impairment
Give a working definition of prions.
- A small proteinaceous infectious particle which resists inactivation by procedures that modify nucleic acids
- In other words, processes that decrease the infectivity of other things dependent on nucleic acids (e.g. bacteria, genes), such as UV radiation, do not affect the prions
Can prions be denatured?
- Yes, but they can renature without any loss of infectivity.
- This can explain why traditional methods of cleaning equipment after surgery may not prevent the spread of prion diseases.
Do prion diseases require a constant production of the endogenous PrP protein?
- Yes, because prion diseases involve deposition of misfolded PrP
- There needs to be continued production, or else the disease progression stops
How can genetics lead to amyloid diseases?
- Genetic mutations affecting protein folding, stability and processing –> misfolded proteins –> amyloid deposition
Describe the characteristics of Alzheimer’s Disease
A slow, progressive, irreversible neuronal loss with progressive cholinergic deficit and intermittent but inexorable cognitive decline.
What is the demographic for Alzheimer’s disease?
It is typically a disease of the elderly, but there is also a rare early onset familial form.
What parts of the brain does Alzheimer’s affect?
- Progressive irreversible damage to sub-cortical and then cortical regions
- This leads to shrinkage of brain tissue
What are the symptoms of Alzheimer’s disease?
- First, degeneration of hippocampus leads to short-term memory loss
- Then there is progressive loss of judgement, control of mood, face recognition, communication, continence
- 4-12 years from diagnosis to death
Do we have good treatments for Alzheimer’s disease?
There are drugs to treat the symptoms, but no curative treatments.
How can Alzheimer’s be diagnosed?
Describe the pathology of Alzheimer’s.
Alzheimer’s is an progressive amyloid disease:
- Extracellular amyloid plaques form between neurons and are composed of fibrils of proteolytic fragments of APP -> They are of unknown pathological significance
- Intracellular neurofibrillary tangles also form and are composed of fibrils of hyperphosphorylated Tau protein (a microtubule-associated protein) in neurons
- These two effects lead to collapse of neuronal structure & connexions
- Local inflammatory responses by glial cells also contribute to the pathology
How and why does amyloid form?
- Amyloid fibrils contain extensive stacked beta sheets, like silk
- The parent protein that the amyloid forms from is often natively alpha helix rich
- The alpha to beta conversion is helped by:
- Proteolysis
- Small side chains
- Unstable native fold
- Denaturing conditions
- Presence of “seed”
- Stabilizing co-factors
Which protein is involved in the pathology of Alzheimer’s disease?
- APP (amyloid precursor protein) is an integral membrane protein
- When it is cleaved in the right place, it forms amyloid beta (Aβ), which forms fibrils that are the main component of amyloid plaques in Alzheimer’s disease
Describe how amyloid is involved in the pathogenesis of Alzheimer’s disease.
- Familial AD and sporadic AD, as well as altered APP, can lead to changes in calcium homeostasis in the cell
- This leads to hyperphosphorylation of TAU (the intracellular protein that aggregates in AD)
- All of these previous effects lead to downstream effects, such as:
- Oxidative damage
- Altered synaptic plasticity
- Excitotoxicity
- Apoptosis/necrosis
- It is also suggested that when the normal pathway for the clearance of amyloidogenic monomers is saturated, then an overflow pathway is opened, which leads to the formation of fibrils and dysfunction
Describe which part of the cell amyloid plaques associate with in Alzheimer’s disease.
Cell membrane -> It exhibits some spontaneous channel activity.
How is chronic inflammation involved in the pathology of Alzheimer’s disease?
- Scavenger receptor enable uptake of amyloid by microglial cells
- These then release cytokines and proteases
- When the microglial cells’ lysosomes become full, they regurgitate the toxic processed amyloid fragments
- Released partially digested fibril components form toxic extracellular species that bind to and damage the plasma membrane of neighbouring cells leading to bystander killing
How can the degree of chronic inflammation in Alzheimer’s disease be assessed?
- Microglial cells produce insulin-degrading enzyme (IDE), which degrades amyloid monomers in the brain.
- The levels of this tell you about the level of inflammation.
What are some treatment approaches for amyloid diseases?
General approaches:
- Immunization with precursor to aid clearance (autoimmunity)
- Inhibition of endoproteases that release amyloidogenic fragments
- Metal ion chelation
- Inhibitors of fibril formation (NB Perhaps inhibition of oligomer formation)
Specific approaches for AD:
- Anticholinesterases (Three licensed for AD)
- Memantine (NMDA receptor antagonist)
- Gamma secretase inhibitors (so far all have failed at Phase III trials)
- Beta secretase inhibitors (problems with oral availability, BBB penetration)
- Passive immunisation against amyloid proteins (increase clearance)
- Anti-inflammatory drugs (Glial cytoprotection)
- Anti-tau approaches (experimental)
What neurons are most severely affected in Alzheimer’s disease?
Cholinergic
What is another name for Alzheimer’s disease?
Senile dementia
