Neurodegenerative diseases

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Neurodegenerative diseases

• Dr.HAZAR
• 2011

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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

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• pharmacological approaches to compensation for
  neuronal loss (applicable mainly to AD and PD).

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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.

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• 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.

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• 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.

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Disease Protein Characteristic pathology Notes
Alzheimer's disease ß-Amyloid (Aß) Amyloid plaques Aßmutations occur in rare familial forms of Alzheimer's disease
Tau Neurofibrillary tangles Implicated in other pathologies ('tauopathies' as well as Alzheimer's disease
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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).

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• 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

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• 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

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• Excitotoxicity due to environmental chemicals may
  contribute to some neurodegenerative disorders.
• Measures designed to reduce excitotoxicity
  include the use of glutamate antagonists, calcium
  channel-blocking drugs and free radical
  scavengers none are yet proven for clinical use.

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2011Memory and learning-1

• Dr.HAZAR

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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.

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Declarative vs. procedural memory

• Declarative memory (explicit memory)
• facts
• dates
• events
• Hippocampus is critical
• Procedural memory (non-declarative/implicit)
• how to perform an act (ride a bicycle)
• basal ganglia (dorsal striatum / caudate-putamen)
  is critical

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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).

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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.

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• 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.Ms 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.

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• 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.

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• 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 couldnt convert
  this information into long-term memories.

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• 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.

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• 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.

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• 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

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• 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.

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• 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.

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• 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.

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• 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.

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• 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.

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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

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• 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.

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Gene transcription, translation, and memory

• DNA is transcribed to produce RNA
• RNA is translated to produce protein
• DNA -gt RNA -gt 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).

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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)

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• Drugs that increase synaptic transmission are
  "agonists".
• Drugs that block or reduce synaptic transmission
  are "antagonists".

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• 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

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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.

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• 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.

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• Loss of intellectual ability with age is
  considered to be a normal process, rate and
  extent of which is very variable

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• . 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.

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• 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

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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 ß-amyloid
  protein (known as Aß),
• 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.

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• 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 AD-like dementia
  occurs in association with overexpression of APP.
  

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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.

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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
  side-effects, 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

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• donepezil, which is not hepatotoxic
• rivastigmine, a longer-lasting drug that is
  claimed to be CNS selective and, therefore, to
  produce fewer peripheral cholinergic side-effects
  
• 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

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• 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.

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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 Aß fragment of
  amyloid precursor protein (APP), a normal
  neuronal membrane protein, produced by the action
  of ß- and ?-secretases. AD is associated with
  excessive Aß formation, resulting in
  neurotoxicity.
• Familial AD (rare) results from mutations in the
  genes for APP, or the unrelated presenilin, both
  of which cause increased Aß 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.

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• 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.