Learning and Memory 2' Amnesia, aging and Alzheimers Disease

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Learning and Memory2. Amnesia, aging and
Alzheimers Disease

• Dr Claire Gibson (cg95_at_le.ac.uk)
• School of Psychology

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Overview

• Amnesia
• Part of the normal aging process?
• Alzheimers Disease (AD)

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Learning and memory

• Changes throughout life
• Aging population
• Decline?

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Amnesia

• Anterograde amnesia
• Retrograde amnesia

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Learning and memory

• Functionally, memory has three stages
• Encoding Consolidation Retrieval
• Involves acetylcholine

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Aging

• Impairments in memory
• Especially declarative
• Less cortical activation during tasks
• Mechanisms
• Loss of neurones/connections
• Cholinergic system
• Representation of information

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Aging

• Loss of neurones/connections
• Gradual loss of brain weight
• Shrinkage of hippocampus
• Age-related decline
• Decline in the acetylcholine system
• Impaired coding by place cells
• Place cells in the hippocampus
• Number of neurones responding the same
• But, neurones encode a smaller amount of
  information

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Alzheimers Disease (AD)

• 1st identified over 100 yrs ago
• A degenerative brain disorder of unknown origin
  that causes progressive memory loss, motor
  deficits, and eventual death.
• Incidence ? as population ages

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AD - occurrence

• 18 million worldwide
• 1 million UK
• 7 aged over 65
• 40 aged over 80
• NHS, carers, support services

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AD early signs

• Normal ageing?
• Blunting of emotional responses
• Social withdrawal
• http//www.healthline.com/hgy-transcripts/memory-a
  nd-alzheimers
• Coping with Forgetfulness in Alzheimers
  Disease

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AD - symptoms

• Memory impairment
• Progressive memory loss
• Initially
• Impairments in episodic and declarative memory

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AD - symptoms

• Loss of function
• Memory
• Insight
• Judgement
• language

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AD - symptoms

• Personality changes
• Apathy
• Most common behavioural change
• Decreased motivation, indifference
• Not related to depression
• Depression
• Depressive symptoms are frequent

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AD later stages

• Time course varies widely
• Onset of symptoms ? death 10 years
• Advanced
• Gross disorientation in time and place
• Total dependence on carer for simple tasks
• Inability to comprehend/communicate
• Little awareness of past or future

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AD - pathology

• Brain atrophy
• Histopathological features
• Senile plaques
• Neurofibrillary tangles
• Synaptic loss
• Selective depletion of neurotransmitter systems
  (e.g. Ach)

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1. Brain Atrophy

• AD severe degeneration of the hippocampus,
  cerebral cortex and ventricular enlargement

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2. Histopathological features

• Senile plaques (amyloid plaques)

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2. Histopathological features

• Neurofibrillary tangles

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Genes and proteins
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b-amyloid production
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b-amyloid production
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b-amyloid production
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AD and amyloid

• AD characterised by amyloid plaques which contain
  mainly aggregated b-amyloid peptide derived from
  amyloid precursor protein (APP)
• In normal healthy individuals, b-amyloid peptides
  are present only in small quantities as soluble
  monomers that circulate in CSF and blood.
• However, in AD patients, their levels are ? and
  they begin to accumulate as insoluble, fibrillar
  plaques.

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3. Synaptic loss

• Extensive
• Depletion of selective neurotransmitter systems
• Acetylcholine (Ach)
• Glutamate
• Serotonin
• Noradrenaline

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4. Depletion of selective neurotransmitter systems

• Neurones that use Ach or glutamate are
  particularly affected
• Also, neurones that utilise serotonin or
  noradrenaline are affected

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Cholinergic neurotransmission
1. Ach production Acetyl CoA choline
Ach and coenyme A
ChAT
Key Acetyl coA acetyl coenzyme A Ach
acetylcholine AchE acetylcholinesterase ChAT
choline acetyltransferase
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Cholinergic hypothesis of AD

• Cholinergic neurones
• Learning, memory, certain aspects of sleep states
  
• Antagonists (e.g. scopolamine)
• Deleterious effect on learning and memory
• Alzheimers Disease
• Degeneration of Ach producing neurones in
  forebrain
• Deficit in Ach producing enzyme

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Causes of AD

• Early-onset
• Hereditary
• lt5 cases
• lt60 -65 yrs
• Late-onset
• Majority cases
• gt60-65 yrs

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Early onset AD

• Caused by gene mutations on chromosomes

• Autosomal dominant inheritance
• If one of these mutated genes is inherited from a
  parent person will almost always develop early
  onset AD

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Late onset AD

• Genes involved
• Apolipoprotein E (apoE)
• ApoE
• gylcoprotein, transports cholesterol in blood,
  plays a role in cellular repair
• On chromosome 19, the apolipoprotein E (apoE)
  gene has three common forms or alleles E2, E3,
  and E4. Thus, the possible combinations in one
  person are E2/2, E2/3, E2/4, E3/3, E3/4, or E4/4.
• E4 one allele of apoE
• Presence of E4 increases risk of developing AD
• Alleles - different forms of the same gene. Two
  or more alleles can shape each human trait. Each
  person receives two alleles, one from each
  parent. This combination is one factor among many
  that influences a variety of processes in the
  body.

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ApoE and b-amyloid

• Normally b-amyloid is soluble
• BUTbecomes insoluble when aopE4 attaches to it
• Therefore, more likely to be deposited in plaques
• Presence of ApoE4
• Increases deposits of b-amyloid and able to
  regulate APP protein from which b-amyloid is
  formed

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AD risk factors

• Most cases of AD are sporadic (i.e. not
  hereditary)
• So, what causes b-amyloid accumulation in those
  cases?
• Head injury, infections, excessive alcohol or
  other drugs, exposure to toxic substances

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Treatment of AD

• Drugs
• cholinesterase inhibitors
• Psychological
• For example
• External memory aids, visual imagery, reality
  orientation

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Cholinergic drugs

• Nearly every drug currently licensed for AD
  cholinesterase inhibitor (ChEI)
• Boosts activity at cholinergic synapses
• (Aricept) UK approved for mild to moderate AD
  in 1997, transiently improves clinical symptoms
  for 6-12 months

AchE acetylcholinesterase
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AD whats the future?

• 1. Lower cholesterol levels
• Two copies of the ApoE4 allele ?? low-density
  lipoprotein
• High levels of low-density lipoprotein
• Linked to risk to AD
• Shown to promote deposition of b-amyloid
• 2. Anti-inflammatory
• Inflammation of brain tissue may play key role in
  development of plaques and tangles
• 3. Antioxidant therapies
• b-amyloid increases number of free radicals
• Brain tissue especially vulnerable to free
  radical damage
• Studies investigating effects of antioxidants
  (e.g. vitamin A, vitamin C, selenium)

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Study guide

• Describe the effects of aging on learning and
  memory
• Describe the key symptoms of AD and their
  progression
• Explain the changes that occur in the brain in AD
• Describe the involvement of b-amyloid in the
  disease process of AD
• Describe the role of the cholinergic system in AD
  and the rationale for the development of
  cholinesterase inhibitors for treating AD
• Whats the future for AD treatment?