Alzheimer’s disease and its treatment Flashcards
Dementia?
A syndrome
Usually of a chronic or progressive nature.
Deterioration in cognitive function- ie the ability for process thought.
What does dementia effect?
Affects memory
Thinking
Orientation
Comprehension
Learning capacity
Lanaguage etc
Consciousness is not effected
What percentage is dementia surferrers caused by alzheimers?
60-70%
Mixed dementia?
Mixture of different types of dementia
What are the numbers of dementia sufferers expected to do every 25 years
Numbers expected to double
AD brain?
Brain has shrunk
Extracellular plaques and intracellular neurofibrillary tangles
Name the 6 important stages of the history of AD research?
- Chloinergic hypothesis
- Discovery of amyloid and tau.
- Oxidative damage.
- Genetic mutations
- Importance of inflammation
- Immunotherapy (antibodies against amyloid)
What happens to an Alzheimers brain?
Severe cell loss.
Spreads from hippocampus right through into the cerebellum and into the spinal cord.
Damge to proteins and protein accumulations
Damage to lipids and inflammation
Late onset alzheimers?
>95% of dementia cases.
>65 yo.
Genetic link with APOE
Early onset Alzheimers disease?
5% of AD cases
Present in >65 yo.
Genetic link with APP, PSEN1, PSEN2
Apolipoprotein E (ApoE)
Major component of very low-density lipoproteins.
Remove excess cholesterol from the blood and carry it to the liver.
Most abundantly produced apoprotein
ApoE role?
Cholesterol and lipid delivery to neurones
Cholesterol transport to the blood to the liver for processing.
What secretes ApoE?
Secreted by glial cells in nascent high-density lipoproteins-like particles.
They contain phospholipids and cholesterol
What is the ApoE concentration in cerebrospinal fluid?
5 µg/ml
ApoE receptors?
LDLR (low desity lipoprotein receptor)
LRP1 (LDLR-related protein)
Undergo endocytosis to transport ligands from the cell surface to intracellular compartments.
ApoE is?
How many forms of it?
glycoprotein
3 common forms (each differ from each other by 1/2 AAs)
ApoE2
ApoE3
ApoE4
ApoE4
Risk of AD is high with one allelle and must greater with two alleles.
60% are ApoE carriers.
Reduces the age of this onset disease.
More extensive plaques and tangles.
Higher CSF concentration of soluble Abeta.
ApoE effects on amyloid?
ApoE contains paritcles sequester Aβ that modulates the cellular uptake of the complex by receptor-mediated endocyotsis.
Modulate Aβ removal from the brain by systemic circulation (transport across the blood-brain barrier)
ApoE facilitates the binding and internalisation of Aβ or its clearance
Targeting ApoE?
Name the 5 Therapeutic approaches
- Conversion of ApoE4 to ApoE3.
- Increase the lipidation.
- Interference interaction between ApoE4 and amyloid beta (Aβ).
- Reversal of the effects of ApoE4.
- Gene transfer
What does ApoE3 and ApoE4 do?
AS1
TREM2?
Triggering receptor expressed on myeloid cells 2.
increaase chance of AD by 3 fold
Rare
Found in microglia.
Related to parkinson’s
PLD3?
little known on function.
Overexpression leads to reduction in Aβ levels
Name the 3 dominatly inherited mutations involved in amyloid processing?
- β-amyloid precusor protein
- PSEN1
- PSEN2
β-amyloid precursor protein (APP)?
Alternatively spliced to produce 3 transcripts
APP695, APP751, APP770
Proteolytic processing of APP leads to production of rfragments and the amyloidogenic pathways.
PSEN1/2?
PSEN1: Located at chromosome 14
PSEN2: located at chromosome 1
PSEN1/2 are important for the γ-secretase complex.
This cleaves APP into Aβ fragments
3 main pathways causing AD?
- The immune system and inflammatory response
- Cholesterol and lipid metabolism
- Endosomal vesicle recycling
What are the 5 major hypotheses that causes AD?
- Cholinergic and glutamatergic
- Amyloid and Tau
- Oxidative stress
- Inflammation
- New targets
Cholinergic hypothesis?
Selective loss of cholinergic projections from hippocampus and frontal campus.
Muscarinic receptor antagonist coud mimic the deficits.
Reversed using AChE inhibitors
Name the 4 current therapeutics?
- Tacrine
- Donepezil
- Galantamine
- Rivastigmine
Tacarine?
Short half life
Need to take 4 times a day (not great with memory problems)
Donepezil?
70Hr half life
Galantamine?
Once a day
Interacts with AChRs
Rivastigmine?
transdermal patch
2x daily
Acetylcholinesterase inhibitors? (AChE inhibitors)
Show consistent, small treatment effects in mild AD
Effects are only temporary.
Effects seen within 4 months
Glutamate/Calcium Dysregulation hypothesis?
Aβ oligomers enhance the presynaptic release of glutamate.
Blocks glutamate uptake by astrocytes though glutamate transporters. Leads to Tau phosphorylation and neuronal death.
Memantine?
A voltage-dependent, non-competitive NMDA receptor antagonist.
Used to manage AD- for peopel that cannot take AChE inhibitors
Amyloid hypthoesis?
3 therpeutic strategies?
- Prevent Aβ production
- Prevent aggregation
- Promote removal
Prevent Aβ production?
beta-secretase inhibitor
gamm-secretase inhibitor
Prevent aggregation?
A β oligomerisation inhibitors.
Tau aggregation inhibitors
Promote removal?
Vaccines
Name the 3 drug trails targeting amyloid processing?
- alpha-secretase inducer
- gamm-secretase inhibitor
- BACE inhibitors:
Tau?
Highly soluble microtubule-binding protein.
Mutations in tau cause frontotemporal dementia.
Hyperphosporylation of tau destablises micrtubules, causing neuronal dysfunction.
Oxidative stress?
Oxygen helps us burn sugar to produce energy.
Need antioxidant defences so it does not damage cell strucutres.
Oxidative stress occurs when free radical production outstrips the ability of the cell to neutralise it
Name the 3 defences against oxidants?
- Glutathione system
- Superoxide dismutase
- Catalase
Name the other 7 causes of oxidative stress?
- Ageing
- Environmental pollution
- Food contaminants
- Cigarettes
- Amyloid
- Inflammation
- Injury
Oxidative stress in AD?
Implicated in the pathology of AD.
Free radical damage to DNA is evident early in AD.
Amyloid and tau patholgies
Alzheimer’s disease (AD) is characterized by extracellular deposition of β-amyloid (Aβ)
intracellular accumulation of hyperphosphorylated, aggregated tau as neurofibrillary tangles
Name the 2 antioxidants that are used as treatment for dementia?
- Vitamin C- does not get into the brain- metabolites of vitamin C (DHA) can get into the brain and protect it from a stroke. DHA is broken down rapidly.
- Vitamin E: does get into the brain however the conc is tighly controlled and even high dosage will not increase the brain concentration.
Inflammation?
Use of anti-inflammatory agents.
People with arthritis less likely to get AD.
NSAIDS did nothing
Statin?
What encodes for nAChRs?
8 alpha (alpha 2->9)
3 beta ( beta2->4)
Heteromeric nAChRs receptor is formed be?
alpha 2-6
beta 2-4 subunits
Homomeric nAChRs is formed by?
alpha 7-9 subunits
80% of nAChRs in the CNS are?
alpha 4 beta 2
10% of the nAChRs in the CNS are?
alpha 7
Early AD:
Aβ and alpa7 nACh recepotr
the expression overlaps.
Aβ induces expressio of the alpha7 nACh receptor
alpha7 nACh receptor activation
Facilitates neurotransmission and synaptic plasticity.
Induces LTP.
Supports learning and memory.
alpha7 interaction with Aβ
found in amyloid plaques.
Can mediate internalisation of aβ
Mediates inflammatory response to Aβ
Blocks amyloid toxicity.
Agonist of the alpha7 nicotinic repector?
Positive and negative effects?
For: conitive enhancing, anti-inflmmatoyr, induces amyloid phagocytosis.
Against: rapid desensitisation
Antagonist for the alpga7 nicotinic receptor:
Positive and negative effects?
For: block adverse effects of Aβ- intracellular accumulation and toxicity.
Against: not cognitive enhacing, block synpatic plasticity.
Modelling MCI
Impairments in olfactory discrimination and odur recognition memory.
Patients with MCI combined with olfactory deficienceies are highly to progress to AD.
OST?
Odour span task.
Based on the digit span task.
Model requires the idenfitication of a novel oduour from an expanding list of previously experienced odours.
Humanin?
The peptide is made by the mitocondria and exported to neighbouring cells to protect amyloid toxicity and ischemic.
Used as a biomarker for early AD.
Reverses defecits of damage and oxidative stress.
Not expressed noramlly- only when there is damage on surviving neurones.
IGFBP3?
Involved in amyloid clearance
Also enduces heart problems and cancer
HNG drug target?
HNG: analog of human increases span length at microscopic doses.
Improves olfactory working memory
Current AD treatments?
Provide limited (9-12mnths) respite in a subpopulation of patients
Afford limited symptomatic relief
Diseas-modifying treatments?
Pathological hallmarks appear to be tombstome marks rather than signpost to the underlying disease.
A model for MCI?
Deficits in olfactory working emory precede amyloid deposition in TG2576
OST examples?
Demonstarte cognitive enhancing.
Nicotine and a7 nACh receptor agonist
Humanin
