AD is a type of dementia
Dementia: set of cognitive symptoms, including memory loss, and difficulties with thinking & problem-solving
AD: loss of cholinergic neurones, which is thought to underlie cognitive deficits
Causes of AD
Dementia can result subsequent to brain trauma, or strokes and other diseases
Otherwise the causes is unknown, we just have factors that are implicated in causing AD
We do know that AD is characterised by a loss in cholinergic activity, degeneration of cholinergic neuron cluster
We also know there are 2 other main characteristics in AD: AB extracellular plaques, and Tau-containing neurofi
Cholinergic Neural Pathway Dysregulation
Irregularity Examples
Degeneration of Nucleus basalis of Meynert in the forebrain NB of M provides main
cholinergic neuron Septohippocampal cluster innervation to the corte
clusters S cluster provides main
hippocampus, and is inv
Nicotinic receptor E.g. presynaptic (Alpha4)2(Beta2)3 subtype, These normally are exp
density reduction or the (Alpha7)5 subtype facilitate NT release, wh
Neurodegeneration in AD affects multiple NTs, but the cholinergic system is what recieves the greate
This progressive degeneration of cholinergic neurones is thought to be associated with A-B plaques,
But the way they actually cause neurodegeneration isn't clear yet
Characteristics of AD
Characteristic Formation
Alpha, Beta or Gamma secretase cleavage of Mutations in TM region
APP with familial AD --> favo
This produces A-B fragments (AB40 or AB42) Gamma-secretase --> le
which tend to aggregate Down syndrome - extra
AB42 more so than AB40 (contains APP) --> leads
Mutations in presenilins
increased Gamma secre
Mutations in ApoE4 -->
aggregated AB
, Extracellular Amyloid Alpha, Beta or Gamma secretase cleavage of Mutations in TM region
Plaques, comprised of APP with familial AD --> favo
A-B protein This produces A-B fragments (AB40 or AB42) Gamma-secretase --> le
which tend to aggregate Down syndrome - extra
AB42 more so than AB40 (contains APP) --> leads
Mutations in presenilins
increased Gamma secre
Mutations in ApoE4 -->
aggregated AB
Neurofibrillary tangles Concerted action of many kinases leads to Most mutations implica
consisting of Tau (in abnormal phosphorylation of Tau, causing Tau's ability to bind to m
hyperphosphorylated dissociation from microtubules, and tau's ability to promote
form) formation of paired helical fragments. (Hong et al, 1998)
This deposition of fragments impairs axonal
transport, which can lead to cell death.
Cell death --> Tau fragments can aggregate,
forming tangles
These tangles may be linked to AB:
AB may activate the kinases that phosphorylate Tau
And then the hyperphosphorylated Tau may favour formation of AB plaques
How AB Plaques may lead to Neurodegeneration
General theory Proposed Mechansim
Apoptosis and AB may induce Ca2+ influx, ROS generation (Ekinci et al, 2000) found t
Inflammation and therefore cause apoptosis of neurones prevented the subsequent
occured after AB toxicity (R
hyperphosphorylation)
They also found that ROS g
hyperphosphorylation led
induced Ca2+ influx into ce
AB activates TRPA1 ion Activation of this channel, on astrocytes, AD model mice that lac
channel induces proinflammatory cytokine release behavioural dysfunction
Suggesting reduced neu
, They also found that ROS g
hyperphosphorylation led
induced Ca2+ influx into ce
AB activates TRPA1 ion Activation of this channel, on astrocytes, AD model mice that lac
channel induces proinflammatory cytokine release behavioural dysfunction
Suggesting reduced neu
ROS-mediated AB can produce oxidative stress, which may (Lu et al, 2013) demons
oligodendrocyte mediate oligodendrocyte dysfunction. breakdown contributes
dysfunction This can lead to myelin breakdown, which slowing
may be involved in the cholinergic (Cai et al ,2014) describ
neurodegeneration inducing oligodendrocy
Zn2+ toxicity Zn2+ (stored in synaptic vesicles) can have Zn2+ is enriched in man
toxic effects, such as activating microglia, patient brains.
leading to innapropriate engulfing of (Lee et al, 2018) demon
synapses, and other neuronal harmful effects oligomers stimulates hip
activation in AB injected
Common theme in AD patients is finding abnormal tau aggregates, including in absence of AB aggreg
In contrast, AB pathology is always accompanied by Tau pathology in AD
So this has led to the idea that AB is upstream of Tau
And that it is tau that is mediating the neurodegeneration seen in AD (largely cholinergic)
(Takashima et al, 1998) added AB to culture cells, led to changes in tau phosphorylation, supporting t
Dementia: set of cognitive symptoms, including memory loss, and difficulties with thinking & problem-solving
AD: loss of cholinergic neurones, which is thought to underlie cognitive deficits
Causes of AD
Dementia can result subsequent to brain trauma, or strokes and other diseases
Otherwise the causes is unknown, we just have factors that are implicated in causing AD
We do know that AD is characterised by a loss in cholinergic activity, degeneration of cholinergic neuron cluster
We also know there are 2 other main characteristics in AD: AB extracellular plaques, and Tau-containing neurofi
Cholinergic Neural Pathway Dysregulation
Irregularity Examples
Degeneration of Nucleus basalis of Meynert in the forebrain NB of M provides main
cholinergic neuron Septohippocampal cluster innervation to the corte
clusters S cluster provides main
hippocampus, and is inv
Nicotinic receptor E.g. presynaptic (Alpha4)2(Beta2)3 subtype, These normally are exp
density reduction or the (Alpha7)5 subtype facilitate NT release, wh
Neurodegeneration in AD affects multiple NTs, but the cholinergic system is what recieves the greate
This progressive degeneration of cholinergic neurones is thought to be associated with A-B plaques,
But the way they actually cause neurodegeneration isn't clear yet
Characteristics of AD
Characteristic Formation
Alpha, Beta or Gamma secretase cleavage of Mutations in TM region
APP with familial AD --> favo
This produces A-B fragments (AB40 or AB42) Gamma-secretase --> le
which tend to aggregate Down syndrome - extra
AB42 more so than AB40 (contains APP) --> leads
Mutations in presenilins
increased Gamma secre
Mutations in ApoE4 -->
aggregated AB
, Extracellular Amyloid Alpha, Beta or Gamma secretase cleavage of Mutations in TM region
Plaques, comprised of APP with familial AD --> favo
A-B protein This produces A-B fragments (AB40 or AB42) Gamma-secretase --> le
which tend to aggregate Down syndrome - extra
AB42 more so than AB40 (contains APP) --> leads
Mutations in presenilins
increased Gamma secre
Mutations in ApoE4 -->
aggregated AB
Neurofibrillary tangles Concerted action of many kinases leads to Most mutations implica
consisting of Tau (in abnormal phosphorylation of Tau, causing Tau's ability to bind to m
hyperphosphorylated dissociation from microtubules, and tau's ability to promote
form) formation of paired helical fragments. (Hong et al, 1998)
This deposition of fragments impairs axonal
transport, which can lead to cell death.
Cell death --> Tau fragments can aggregate,
forming tangles
These tangles may be linked to AB:
AB may activate the kinases that phosphorylate Tau
And then the hyperphosphorylated Tau may favour formation of AB plaques
How AB Plaques may lead to Neurodegeneration
General theory Proposed Mechansim
Apoptosis and AB may induce Ca2+ influx, ROS generation (Ekinci et al, 2000) found t
Inflammation and therefore cause apoptosis of neurones prevented the subsequent
occured after AB toxicity (R
hyperphosphorylation)
They also found that ROS g
hyperphosphorylation led
induced Ca2+ influx into ce
AB activates TRPA1 ion Activation of this channel, on astrocytes, AD model mice that lac
channel induces proinflammatory cytokine release behavioural dysfunction
Suggesting reduced neu
, They also found that ROS g
hyperphosphorylation led
induced Ca2+ influx into ce
AB activates TRPA1 ion Activation of this channel, on astrocytes, AD model mice that lac
channel induces proinflammatory cytokine release behavioural dysfunction
Suggesting reduced neu
ROS-mediated AB can produce oxidative stress, which may (Lu et al, 2013) demons
oligodendrocyte mediate oligodendrocyte dysfunction. breakdown contributes
dysfunction This can lead to myelin breakdown, which slowing
may be involved in the cholinergic (Cai et al ,2014) describ
neurodegeneration inducing oligodendrocy
Zn2+ toxicity Zn2+ (stored in synaptic vesicles) can have Zn2+ is enriched in man
toxic effects, such as activating microglia, patient brains.
leading to innapropriate engulfing of (Lee et al, 2018) demon
synapses, and other neuronal harmful effects oligomers stimulates hip
activation in AB injected
Common theme in AD patients is finding abnormal tau aggregates, including in absence of AB aggreg
In contrast, AB pathology is always accompanied by Tau pathology in AD
So this has led to the idea that AB is upstream of Tau
And that it is tau that is mediating the neurodegeneration seen in AD (largely cholinergic)
(Takashima et al, 1998) added AB to culture cells, led to changes in tau phosphorylation, supporting t
