Transcript 2011neurodegdiseases..

Neurodegenerative diseases
Dr.HAZAR
2011
Neurodegenerative diseases
• The main topics discussed are:
• mechanisms responsible for neuronal
death, focusing on protein aggregation (e.g.
amyloidosis), excitotoxicity, oxidative stress
and apoptosis
• pharmacological approaches to
neuroprotection, based on the above
mechanisms
• pharmacological approaches to
compensation for neuronal loss
(applicable mainly to AD and PD).
PROTEIN MISFOLDING AND AGGREGATION IN
CHRONIC NEURODEGENERATIVE DISEASES
• Many chronic neurodegenerative diseases
involve the misfolding of normal or mutated
forms of physiological proteins. Examples
include Alzheimer's disease, Parkinson's
disease, amyotrophic lateral sclerosis and
many less common diseases.
• Misfolded proteins are normally removed by
intracellular degradation pathways, which
may be altered in neurodegenerative
disorders.
• Misfolded proteins tend to aggregate,
initially as soluble oligomers, later as
large insoluble aggregates that
accumulate intracellularly or
extracellularly as microscopic deposits,
which are stable and resistant to
proteolysis.
• Misfolded proteins often present
hydrophobic surface residues that
promote aggregation and association
with membranes.
• The mechanisms responsible for
neuronal death are unclear, but there is
evidence that both the soluble
aggregates and the microscopic
deposits may be neurotoxic.
Disease
Protein
Characteristic
pathology
Notes
Alzheimer's
disease
β-Amyloid (Aβ)
Amyloid plaques Aβmutations
occur in rare
familial forms of
Alzheimer's
disease
Tau
Neurofibrillary
tangles
Implicated in
other pathologies
('tauopathies'} as
well as
Alzheimer's
disease
Excitotoxicity and oxidative
stress
• Excitatory amino acids (e.g. glutamate)
can cause neuronal death.
• Excitotoxicity is associated mainly with
activation of NMDA receptors, but other
types of excitatory amino acid
receptors also contribute.
• Excitotoxicity results from a sustained
rise in intracellular Ca2+ concentration
(Ca2+ overload).
• Excitotoxicity can occur under
pathological conditions (e.g. cerebral
ischaemia, epilepsy) in which excessive
glutamate release occurs. It can also occur
when chemicals such as kainic acid are
administered.
• Raised intracellular Ca2+ causes cell death
by various mechanisms, including
activation of proteases, formation of free
radicals, and lipid peroxidation. Formation
of nitric oxide and arachidonic acid are
also involved
•Various mechanisms act normally to protect
neurons against excitotoxicity, the main ones
being Ca2+ transport systems, mitochondrial
function and the production of free radical
scavengers.
•Oxidative stress refers to conditions (e.g.
hypoxia) in which the protective mechanisms
are compromised, reactive oxygen species
accumulate, and neurons become more
susceptible to excitotoxic damage
•Excitotoxicity due to environmental
chemicals may contribute to some
neurodegenerative disorders.
•Measures designed to reduce
excitotoxicity include the use of
glutamate antagonists, calcium channelblocking drugs and free radical
scavengers; none are yet proven for
clinical use.
2011Memory and learning-1
Dr.HAZAR
Types of memory
• There is general agreement that there
are several different types of memory,
each of which is predominantly in a
different part of the brain.
Declarative vs. procedural memory
• Declarative memory (explicit memory):
–
–
–
–
facts
dates
events
Hippocampus is critical
• Procedural memory (nondeclarative/implicit):
– how to perform an act (ride a bicycle)
– basal ganglia (dorsal striatum / caudate-putamen)
is critical
Alzheimer'
• Patients with Alzheimer's disease are
unable to learn or remember ordinary
facts (declarative memory) but are
normal or nearly normal at learning and
remembering how to do things
(procedural memory).
Memory and the hippocampus
• In 1950, a young man, known now by
his initials, H.M. underwent brain
surgery in Hartford, Connecticut.
• H.M. was one of several patients in
whom parts of the temporal lobe were
removed in an effort to control
epilepsy.
• The temporal lobe is one of the four
major divisions (lobes) of the brain, and
is often the place in the brain attacked
by epilepsy.
• In H.M’s case, temporal lobe areas were
removed on both sides of his brain.
• After the surgery, his epilepsy was
better, but he no longer had the ability
to acquire new memories.
• H.M became probably the most famous
case in neurological history, and has
been the subject of many studies.
• Much of the initial work was carried out
by Brenda Milner and her colleagues in
Montreal.
• Milner found that, although H.M could
recall many of the events of his earlier
life, he was unable to form new
memories for experiences that
occurred after the surgery.
• He could remember things for a few
seconds (short-term memories) but he
couldn’t convert this information into
long-term memories.
• Analysis of H.M.’s lesion, based on the
surgical report, indicated that the main
temporal lobe areas affected were the
hippocampus, amygdala, and parts of
the surrounding cortex.
• By comparing H.M.’s lesion with those
in other patients, it seemed that the
hippocampus was the area damaged
most consistently in memory deficits.
• At first, it was thought that H.M. had lost
all ability to acquire new memories.
• However, it was found that he could learn
certain tasks.
• Much is now known about the
hippocampus, but we will mention just a
few points.
• Information about the external world comes
into the brain through sensory systems that
relay signals to the cortex, where sensory
representations of objects and events are
created
• Outputs of each of the cortical sensory
systems converge in parahippocampal
region (also known as the rhinal cortical
areas) which surrounds the hippocampus.
• The parahippocampal region integrates
information from the different sensory
modalities before sending it to the
hippocampus proper.
• The hippocampus and parahippocampal
region make up what is now called the
medial temporal lobe memory system,
which is involved in explicit or declarative
memory.
• The connections between the hippocampus
and the neocortex are all more or less
reciprocal
• The pathways that take information from
the neocortex to the rhinal areas and then
into the hippocampus are mirrored by
pathways going in the opposite direction.
• Cortical areas involved in processing a
stimulus can thereby also participate in the
long-term storage of memories of that
stimulus.
• The rhinal areas serves as convergence
zones, brain regions that integrate
information across sensory modalities and
create representations that are independent
of the original modailty.
• As a result, sights, sounds, and smells can be
put together in the form of a global memory
of a situation.
• Many researchers believe that explicit
memories are stored in the cortical systems
that were involved in the initial processing
of the stimulus, and that the hippocampus is
needed to direct the storage process.
Early experiments on drug
effects on memory
• Certain post-training treatments can
modulate memory storage in ways that
enhance or prevent retention.
• First observed with stimulant drugs
– strychnine (very low doses)
– amphetamine
– caffeine
• Early studies showed that drugs that
inhibit protein synthesis also inhibit
long-term memory formation.
• Several inhibitors of RNA synthesis or
protein synthesis block long-term
memory, but do not affect short-term
memory.
Gene transcription, translation, and
memory
• DNA is transcribed to produce RNA
• RNA is translated to produce protein
• DNA -> RNA -> protein
• Transcription factors are proteins that
regulate what genes are transcribed
(expressed).
• Transcription factors typically bind near the
promoter region of a gene (the on/off switch).
How drugs act on synapses
• Neurons communicate with each other at
synapses using chemical neurotransmitters.
• This provides the bases for drugs (and
poisons) to affect synaptic transmission.
• Drugs with chemical properties similar in
some way to those of neurotransmitters can
act on synapses to alter behavior and
thoughts (psychotropic or psychoactive
drugs)
• Drugs that increase synaptic
transmission are "agonists".
• Drugs that block or reduce synaptic
transmission are "antagonists".
• About 25 neurotransmitters are known
in the mammalian brain.
• Most psychoactive drugs act on the
synapses of a single neurotransmitter.
• These synapses often occur in
different, functionally unrelated parts of
the brain, controlling many different
behaviors
• The psychological actions of drugs can
be quite complex and difficult to predict
To affect the brain, drugs must
cross the blood-brain barrier
• Access to the brain from the circulatory
system is controlled by the blood-brain
barrier (BBB).
• This barrier is made up of a layer of cell
surrounding the blood vessels that
supply the brain.
• These cells determine the degree to
which substances in the blood can
enter the brain.
• Fat-soluble substances (e.g., alcohol) cross
the BBB more easily than water –soluble
substances.
• Drugs and hormones with large molecular
weights do not easily pass the BBB.
• Some substances, including glucose and
insulin, are actively transported into the
brain.
• The degree to which drugs cross the BBB is
critical to their effects on memory.
• Loss of intellectual ability with age is
considered to be a normal process, rate
and extent of which is very variable
• . Alzheimer's disease (AD) was
originally defined as presenile
dementia, but it now appears that the
same pathology underlies the dementia
irrespective of the age of onset. AD
refers to dementia that does not have
an antecedent cause, such as stroke,
brain trauma or alcohol. Its prevalence
rises sharply with age, from about 5%
at 65 to 90% or more at 95.
• Until recently, age-related dementia was
considered to result from the steady loss of
neurons that normally goes on throughout
life, possibly accelerated by a failing blood
supply associated with atherosclerosis.
Studies since the mid-1980s have, however,
revealed specific genetic and molecular
mechanisms underlying AD (reviewed by
Selkoe, 1993, 1997), which have opened new
therapeutic opportunities
PATHOGENESIS
AD is associated with brain shrinkage, and
localised loss of neurons, mainly in the
hippocampus and basal forebrain.
Two microscopic features are characteristic :
1. Extracellular amyloid plaques, consisting of
amorphous extracellular deposits of βamyloid protein (known as Aβ),
2. Intraneuronal neurofibrillary tangles,
comprising filaments of a phosphorylated
form of a microtuble-associated protein
(Tau). These appear also in normal brains,
though in smaller numbers.
• The early appearance of amyloid deposits presages
the development of AD, though symptoms may not
develop for many years. Altered processing of
amyloid protein from its precursor (APP; see below)
is now recognised as the key to the pathogenesis of
AD. This conclusion is based on several lines of
evidence, particularly the genetic analysis of certain,
relatively rare, types of familial AD, in which
mutations of the APP gene, or of other genes that
control amyloid processing, have been discovered.
The APP gene resides on chromosome 21, which is
duplicated in Down's syndrome, in which early ADlike dementia occurs in association with
overexpression of APP.
Loss of cholinergic neurons
• Though changes in many transmitter systems have
been observed, mainly from measurements on
postmortem AD brain tissue, a relatively selective
loss of cholinergic neurons in the basal forebrain
nuclei is characteristic. This discovery, made in
1976, implied that pharmacological approaches to
restoring cholinergic function might be feasible,
leading to the use of cholinesterase inhibitors to
treat AD .Choline acetyltransferase (CAT) activity in
the cortex and hippocampus is reduced
considerably (30-70%) in AD but not in other
disorders such as depression or schizophrenia;
acetylcholinesterase activity is also greatly reduced.
Muscarinic receptor density, determined by binding
studies, is not affected, but nicotinic receptors,
particularly in the cortex, are reduced.
Cholinesterase inhibitors
• Tacrine was the first drug approved for treating
AD, on the basis that enhancement of
cholinergic transmission might compensate for
the cholinergic deficit.
• Tacrine is far from ideal; it has to be given four
times daily and produces cholinergic sideeffects, such as nausea and abdominal cramps,
as well as hepatotoxicity in some patients. Later
compounds, which have limited efficacy but are
more effective than tacrine in improving quality
of life, include:
• donepezil, which is not hepatotoxic
• rivastigmine, a longer-lasting drug that is
claimed to be CNS selective and, therefore,
to produce fewer peripheral cholinergic sideeffects
• galanthamine, an alkaloid from plants of the
snowdrop family, which is claimed to act
partly by cholinesterase inhibition and partly
by allosteric activation of brain nicotinic
acetylcholine receptors
• Other drugs Dihydroergotamine was
used for many years to treat dementia.
It acts as a cerebral vasodilator, but
trials showed it to produce little if any
cognitive improvement. 'Nootropic'
drugs, such as piracetam and
aniracetam, improve memory in animal
tests, possibly by enhancing glutamate
release, but are probably ineffective in
AD.
Dementia and Alzheimer's
disease
• Alzheimer's disease (AD) is a common age-related dementia,
distinct from vascular dementia associated with brain
infarction.
• The main pathological features of AD comprise amyloid
plaques, neurofibrillary tangles and a loss of neurons
(particularly cholinergic neurons of the basal forebrain).
• Amyloid plaques consist of the Aβ fragment of amyloid
precursor protein (APP), a normal neuronal membrane protein,
produced by the action of β- and γ-secretases. AD is
associated with excessive Aβ formation, resulting in
neurotoxicity.
• Familial AD (rare) results from mutations in the genes for APP,
or the unrelated presenilin, both of which cause increased Aβ
formation.
• Neurofibrillary tangles comprise aggregates of a highly
phosphorylated form of a normal neuronal protein (Tau). The
relationship of these structures to neurodegeneration is not
known.
• Loss of cholinergic neurons is believed to account
for much of the learning and memory deficit in AD.
• Anticholinesterases (tacrine, donepezil,
rivastigmine) give proven, though limited, benefit in
AD.
• Many other drugs, including putative vasodilators
(dihydroergotamine), muscarinic agonists (arecoline,
pilocarpine ) and cognition enhancers (piracetam,
aniracetam), give no demonstrable benefit and are
not officially approved.
• Certain anti-inflammatory drugs, and also clioquinol
(a metal chelating agent), may retard
neurodegeneration and are undergoing clinical
evaluation.