L15 - alzheimers Flashcards
what are the two major treatments for alzheimers
anticholinesterases
NMDA receptor antagonists
only symptom treating, as the cause of disease is unknown
describe the process of formation of senile plaques (ß amyloid plaques)
- ß amyloid precursor protein is present in the fatty membranes that surround neurones
- Normally, alpha and gamma secretases cleave this protein (within the ß amyloid sequence) which doesn’t produce the ß amyloid protein
However, a disorder in processing this amyloid precursor protein leads to the formation and accumulation of ß amyloid protein in the extracellular space.
This is an adhesive molecule so over time the proteins come together to form a plaque
It is not understood why some of the ß amyloid is internalised and why some is in extracellular space
where is the ß amyloid precursor protein usually found
in fatty membranes surrounding neurones
what happpens to the ß amyloid precursor protein in the normal, healthy situation
alpha and gamma secretases cleave it within the ß amyloid sequence, so that the ß amyloid protein isnt formed
what cleaves the ß amyloid precursor protein
alpha and gamma secretases
why do ß amyloid proteins form plaques?
they are adhesive molecules and so they ‘stick’ together
do ß amyloid plaques only form in alzheimers patients?
no they naturally form with age, but it happens to a much larger extent in AD patients
how is ß amyloid plaque formation in healthy individuals usually prevented?
by surface endocytosis of the ß amyloid proteins to prevent accumulation in extracellular space
what could be the cause of this abnormal ß amyloid precursor protein processing
- genetic -> more than 50 mutations in APP gene can cause early onset AD. these mutations either increase ß amyloid protein production or produce longer, stickier versions of it
- environmental -> HBP and high cholesterol seem to increase risk of AD
what can mutations in the ß amyloid precursor protein gene lead to? and how does this relate to AD
either
- increased production of ß amyloid protein
- production of a longer, stickier ß amyloid protein
what environmental factors correlate with increased risk of AD and why?
HBP
high cholesterol levels
unknown whether this causes increased ß amyloid protein production or increased deposition in extracellular space
why are amyloid plaques harmful?
→ inflammation occurs around the plaques which is toxic to neighbouring neurones, leads to their destruction
this impairs communication between neurones (via damage to dendrites and axons) as well as neurones being surrounded by dead neurones
→ can lead to excitotoxicity by: increasing vulnerability of neurones to glutamate via activation of NMDA receptors
(NMDA activation can also affect tau expression and function)
->cause changes in synaptic ACh transmission
what is the significance of tau proteins
tau proteins bind to microtubules and regulate their stability
they are important in maintenance of neuronal activity
how is the normal fucntioning of tau proteins altered in AD
- in AD, there is presence of abnormally phosphorylated tau proteins which causes them to tangle
- they are then unable to bind and regulate microtubbule stability
- this can lead to collapse of microtubules and destruction of neurones
describe neurofibrillary tangles
- made up of tangles of abnormally phosphorylated tau proteins which form filaments
density of NFTs in brain is directly related to severity of alzheimers
unclear why tangles form
comment on genetic influence of Tau tangling
there are genetic forms of tau that are more likely to form tangles.
supports genetic influence in AD
what is importannt to note about ß amyloid plaques in AD
deposition of ß amyloid plaques alone is not sufficient for the neuropathy seen in AD, because
- plaques are seen in normal ageing brain and some elderly patients with them experience no cognitive impairment
there is some evidence that the neurotoxic environment created by amyloid plaques can result in NFTs
there is some evidence that the neurotoxic environment created by amyloid plaques can result in NFTs
describe cholinergic degeneration in AD
degeneration of neurones in the nucleus basalis meynert (the origin of major cholinergic projections to the neocortex) has been shown to occur in early AD
AD involves substantial loss of transmission in cholinergic system (neurones and loss of choline transferase required for ACh synthesis)
what effects on the cholinergic system have been observed in AD
- loss in cholinergic transmission through degeneration of neurones in the nucleus basalis meynert (the origin of major cholinergic projections to the neocortex)
- loss of choline acetyltransferase (needed for ACh synthesis)
what is the nucleus basalis meynert
(the origin of major cholinergic projections to the neocortex)
what are the brain regions most affected by cholinergic degeneration in AD
cortex
hippocampus
basal forebrain (severly)
ventral striatum
these are regions we would expect to find plaques and NFTs
explain how cholinergic degradation leads to symptoms of alzheimers
cholinergic system is important in cognitive processes including learning and memory
severe degeneration in the basal forbrain nuclei means diminished output from the hippocampus and neocortex (both major sites inolved in cognition and memory)
describe mechanism of anti-cholinesterases as treatment for AD
- reduce breakdown of ACh by acetylcholinesterase, increasing [ACh] in cleft
- this enhances neurotransmission and ability to activate receptors on alive neurones
does Anticholinesterase treatment (increasing [ACh] in cleft) cause receptor sensitisation?
No
AD treatment with anti-cholinesterases is only effective for 1-3 years, why?
because it doesnt alter disease progression, neurones continue to die until eventually increasing [ACh] doesnt help as there are no functioning cholinergic neurones
describe evidence for role of AChE in pathogenesis of AD?
- there is a small structural motif within AChE that interacts with deposited B amyloid proteins promoting fibril formation
- AChE staining around B amyloid plaques is very storng
examples of an AChE inhibitor
donepezil
rivastigmine
galantamine
describe features of the AChE inhibitor donepezil
high selectivity for CNS AChE (less peripheral side effects)
upregulates nAChRs in cortical neurones
side effects of donepezil (AChE inhibitor)
GI disturbances
loss of appetite
muscle cramps
explain the influence of the glutamatergic system in AD
glutamatergic excitatory system critical in brain for learning and memory
glutamate excitotoxicity (via /NMDA receptor activation) can cause neuronal cell death
define glutamate excitotoxicity in terms of AD
inapropriately sustained glutamate mediated activation of NMDA receptors leading to neuronal cell death
what effect do B amyloid plaques have on the glutamatergic system
there is evidence that:
- B amyloid plaques can increase vulnerability of neurones to glutamate, leading to glutamate excitotoxicity via interaction with NMDA receptors
how is Tau affected by the glutamatergic system?
NMDA receptor activation can affect tau expression and function
what drugs can target glutamatergic system to treat AD
NMDA receptor antagonists eg memantime - a non competitive NMDA channel blocker
describe function of NMDA receptor antagonists eg memantime
- block the NMDA receptor preventing excitotoxicity (and especially destruction of of cholinergic neurones) - blocks low, weak activity associated with tonic levels of glutamate. high levels can still activate the receptor
- at low concs it can promote synaptic plasticity
what is synaptic plasticity
ability of synapses to strengthen or weaken
memantine and donezepil often given in combination
side effects of memantine
usually well tolerated
dizziness
confusion
headaches
what other receptors does memantine act on and what effect does this have in AD
5-HT3 receptor antagonist, whihch may have beneficial effect on cognition and memory
explain M1 muscarinic agonists in AD treatment
M1 receptor activation does the following in AD
- increases soluble APP release via increase in alpha secretase (less amyloid formation)
- decreases tau phosphorylation
- alleviates cognitive deficits in cotex and hippocampus in mouse models of AD
- aids cholinergic defecit (via receptor activation instead of ACh)
what effect does M1 activation in AD have on tau
decreases its phosphorylation
what effect does M1 activation in AD have on plaque formation
increases alpha secretase levels and so increases release of soluble amyloid precursor protein instead of B amyloid protein
how are M1 receptors affected in AD
-coupling of M1 receptors to G proteins in neocortex is impaired (less effective receptor activation)
how are M2 antagonists used in AD tretament
M2 antagonists reduce the negative feedback inhibiton of ACh release - leading to increased M1 receptor activation
what evidence is there for the (2x a4) (3x B2) nAChR being neuroprotective?
in regions of brain with high levels of B amyloid, a4B2 receptor mediated cholinergic responses were impaired
what evidence is there for the involvement of a7 nAChRs in AD
- In regions of the brain that had high levels of ß amyloid, the cholinergic response by a7 receptors is impaired
- Protects against toxicity of ß amyloid plaques
what evidence is there for the significance of nicotine in AD
- nicotine upregulates expression of nAChRs
- in cultured neurones (with a7 / a4B2 receptors) nicotine prevents B amyloid induced apoptosis
- other studies have shown nAChR activation results in increases B amyloid plaque mediated tau phosphorylation
modulation of different cholinergic receptors might play different roles in AD pathology at different stages of the disease
what are the limitations of current AD treatments
- disease is progressive so treatments must adapt to differnet stages
- no single model that can well mimic all stages of the disease
- dont know the entire pathology / origin of the disease (so no disease modifying treatments have been developed)
promising future AD treatments?
secretases
B amyloid antibodies
what would an ideal disease modifying therapy target?
prevention of B amyloid formation (secretases etc)
prevent NFTs (prevention of tau phosphorylation) (kinase inhibitors)
decrease glutamate excitotoxicity
symptoms of AD
amnesia -> loss of memory (short and long term)
aphasia -> simplified language use
apraxia
AD can also cause other associated symptoms such as mood disorders, depression
treated with antidepressants, anxiolytics etc
