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Alzheimer Disease

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Title: Alzheimer Disease


1
Alzheimer Disease
2
Learning Objectives
  • The student should be able
  • 1.To be familiar with the Clinical description of
    AD
  • 2. Acquire knowledge of Genetics involve.
  • 3. Pathophysiology
  • 4. Biomarkers and animal models
  • 5. Therapeutic approaches (Match Hypothesis)

3
The year 2006 is the centenary of the famous
presentation of Alois Alzheimer which first
described the neuropathology of Alzheimers
disease (AD).
  • Alzheimer described the results of his postmortem
    studies on a 51-year-old-female patient known as
    Auguste D., who had suffered from a progressive
    presenile dementia
  • Described a relatively young patient who had
    developed a rapid loss of memory and had become
    disoriented in time and space.

Alois Alzheimer (b. 1864d. 1915)
4
Alois Alzheimer
  • As the illness progressed, she became bedridden
    and incontinent. She died four and a half years
    after the onset of illness.
  • Post-mortem examination revealed an evenly
    atrophic brain with striking neurofibrillary
    pathology.
  • Alzheimer also described the presence of unusual
    deposits in the cortex that were refractory to
    staining.

His famous paper (Alzheimer 1907)
5
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6
The Anatomical Hallmark of Alzheimers
Pathology Amyloid Plaques and Neurofibrillary
Tangles in Brain
Also generally reduced brain volume, especially
in entorhinal cortex and hippocampus
7
Alzheimers Disease
  • Alzheimers disease is the most common form of
    dementia. accounting for 5060 of all cases.
  • Dementia is a syndrome that exhibits impaired
    short-term and long term memory as its most
    prominent feature.
  • Forgetfulness is the primary complaints of
    patients.

8
1. Symptoms of Alzheimers Disease
  • AD begins with a pure impairment of cognitive
    function.
  • mild cognitive impairment does not always lead
    to dementia.
  • 2. Progression
  • AD begins slowly. At first, the only symptom may
    be mild forgetfulness.
  • In this stage, people may have trouble
    remembering recent events, activities, or the
    names of familiar people or things.
  • They may not be able to solve simple math
    problems.
  • They may begin to repeat themselves every few
    minutes in conversation.
  • B. In the middle stages of AD, individuals may
    forget how to do simple tasks, like brushing
    their teeth or combing their hair.
  • They can no longer think clearly.
  • They begin to have problems speaking,
    understanding, reading, or writing.
  • C. Late stage AD patients may become anxious or
    aggressive, or wander away from home.
  • Eventually, patients need total care.

9
Incidence of Alzheimers disease (AD)
AD is the most common degenerative brain disease
(est. 5 million USA, 25 million globally) Risk
Factors age
65-74 75 80 gt85
5 10 20 50
(However, AD is not considered a normal part of
aging). The more common form of AD, known as
late-onset or sporadic AD, occurs later in life,
with no obvious inheritance pattern. However,
several risk factor genes may interact with each
other to cause the disease. Most common risk
factor gene identified so far for late-onset AD,
is a gene that makes one form of apolipoprotein E
(apoE). ApoE4 (prevalence 16) is the risk
factor gene, 3-4 fold dominant increase. Familial
AD, which is rarer, usually starts at age 30 -
60.
10
Red circles presenilin 1 and APP mutations
associated with familial AD
presenilin 1 is part of ?-secretase, a
membrane-associated protease
Hardy and Selkoe, 2002, Science
11
All known genetic risk factors predisposing to
Alzheimers disease Increase accumulation of Aß
peptides
Chromosome Gene defect Phenotype
21 ß-APP mutations ?All Aß peptides, or Aß40 peptides A673T? Aß peptides, AD, cognitive decline
19 ApoE4 polymorphism (e4 allele) ?Density of Aß plaques vascular deposits
14 Presenilin 1 mutation ?Production of Aß42 peptides
1 Presenilin 2 mutation ?Production of Aß42 peptides
6 TREM2 ?Density of Aß plaques


The precise meaning of the amyloid hypothesis
changed over the years, and differs among
scientists. Originally, it was thought that the
actual amyloid is pathogenichence the term
amyloid hypothesis. The more current version of
this hypothesis posits that Aß (especially Aß42)
microaggregatesalso termed soluble Aß
oligomers or Aß-derived diffusible ligands
(ADDLs)constitute the neurotoxic species that
causes AD Sheng, 2012 Abnormal states of tau
mediate some effects of ß-amyloid. This stage may
be distal to the more toxic dimers and oligomers.
12
There are tauopathies as well, Mutations in tau
protein. These cause frontotemporal dementia
with parkinsonism, linked to Chromosome 17
13
Animal models mice overexpressing APP,
especially with AD-associated mutations.
14
  • Biomarkers for AD.
  • Only an autopsy is conclusive, but progress in
    two areas

1. Cerebrospinal fluid analyses of tau,
phospho-tau at position 181, and Aß42. Individual
values, or ratios among these.
Positive
Negative
A negative scan indicates sparse to no neuritic
plaques and is inconsistent with a
neuropathological diagnosis of AD at the time of
image acquisition a negative scan result reduces
the likelihood that a patients cognitive
impairment is due to AD. A positive scan
indicates moderate to frequent amyloid neuritic
plaques neuropathological examination has shown
this amount of amyloid neuritic plaque is present
in patients with AD, but may also be present in
patients with other types of neurologic
conditions as well as older people with normal
cognition. Florbetapir is an adjunct to other
diagnostic evaluations.
15
Cholinergic hypothesis
  • The cholinergic hypothesis in Alzheimers disease
    states that degeneration of cholinergic neurons
    in the basal forebrain nuclei causes disturbances
    in presynaptic cholinergic terminals in the
    hippocampus and neocortex, which is important for
    memory disturbances and other cognitive symptoms.
  • Potentation of the activity of the central
    cholinergic pathway is one strategy for the
    symptomatic treatment of cognitive dysfunction in
    AD.

16
Acetylcholinesterase inhibitorsTacrine
  • Tacrine, the first agent approved for symptomatic
    treatment of mild to moderate AD
  • Inhibit both acetylcholineesterase and
    butyrylcholineesterase (BuCHE)
  • Low bioavailability, short half-life (multiple
    doses)

17
Tacrine
  • Side effect
  • Nausea, vomiting , diarrhea, abdominal pain.
  • Elevation of alanine aminotransferase (ALT) levels

18
Donepezil
  • Second generation cholinesterase inhibitors
  • Selective Acetylcholinestearse than (BuCHE)
  • Completely bioavailability, once daily
  • Side effect cholinergic activity (nausea,
    diarrhea, headache)

19
Rivastigmine
  • Inhibit activity of both AChE and BuChE by
    binding to esteratic site of both enzymes and
    slowly dissociates.
  • Called Pseudo-irreversible
  • Twice daily

20
Galantamine
  • Inhibit AChE.
  • allosteric modulation of nicotinic acetylcholine
    receptors
  • It stimulates nicotinic receptors at a site
    distinct from that stimulated by acetylcholine
    action that does not rely on the presence of Ach
  • Metabolized by CYP2D6

21
Glutamate theory
  • Glutamate is the major excitatory
    neurotransmitter in the central nervous system.
  • An over activation of glutamate receptors, and
    particularly of N-methyl-D-aspartate (NMDA)
    receptors, leads to an immediate rise in calcium
    ions (cell death)
  • Memantine blocks glutamate-mediated
    excitotoxicity

22
Glutamate theory
  • Memantine was approved for the treatment of
    moderate and severe AD case as early as in
    February 2002.
  • The basis for this approval was the result of two
    randomized placebo-controlled clinical studies
    that have showed a positive effect in a later
    stage of this disease (Reisberg et al. 2003).
  • It only affects pathophysiological conditions
    (NMDA receptor over activation) and leaves
    physiological neurotransmission unchanged.

23
The amyloid cascade hypothesis
  • Amyloid precursor protein (APP) is a protein
    containing 770 amino acids
  • Cleaved into peptides by three enzymes alpha,
    beta and gamma secretase.
  • APP is mainly formed by a two step process

24
If alpha secretase initially cleaves APP,
alpha-soluble APP (a-sAPP) is formed and
eventually becomes a benign peptide.
25
When beta secretase initially cleaves APP, it
becomes beta soluble APP (ß-sAPP). ß -sAPP can
subsequently be cleaved by gamma secretase at two
different sites producing harmful peptides such
as Ab 40 and Ab 42.
26
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27
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28
The amyloid cascade hypothesis
  • There are two types of beta secretase beta-site
    APP cleaving enzyme 1,2 (BACE 1, BACE 2)
  • Two forms of gamma secretase (presenilin 1,
    presenilin 2).

29
Inherited Genetic Factors
  • Mutations in genes involved in amyloid beta
    processing (seen in familial early onset cases)
  • Variation in a gene (apolipoprotein) that
    produces a protein essential for clearing
    cholesterol and other molecules out of the
    bloodstream seen in the general population
    (sporadic AD cases)

30
  • Less than 10 of the AD cases are autosomal
    dominantly inherited and are linked to one of
    three different chromosomes.
  • To date, mutations in the following genes have
    been described to be causative for early onset AD
  • presenilin-1 gene on chromosome 14,
  • presenilin-2 gene on chromosome 1
  • amyloid precursor protein gene on chromosome 21.

31
Alzheimer and genetics
  • People that carry mutations in any one of these
    genes usually experience a very early onset of
    AD, well below 60 years of age

32
Potential target in the future
  • ß-secretase inhibitors
  • ?-Secretase inhibitors

33
Metal Ions and Amyloid ß proteins
  • Aß itself can act as a metalloprotein displaying
    high affinity for copper (Cu2) and zinc (Zn2).
  • Interaction between amyloid and metal ions might
    mediate amyloid aggregation and amyloid nerve
    cell toxicity

34
Ion chelators
  • clioquinol is a hydrophobic compound that acts
    as a copper and zinc chelator
  • It can readily cross the blood brain barrier
  • Clioquinol was used decades ago as an oral
    antiamoebic compound, but it has been withdrawn
    from the market because of possible neuropathic
    side-effects.
  • Phase II clinical trial

35
Disease-related changes of the tau
  • tau is a protein involves binding and
    stabilization of microtubule structure and
    function.
  • The microtubule network in the cell is required
    for the transport of proteins.

36
Tau, calpains and apoptosis
  • cyclin-dependent kinase 5 (cdk5), which promote
    phosphorylation of tau
  • p35 is a neuron-specific activator of cdk5
  • conversion of p35 into p25 by calpain-dependent
    proteolysis causes prolonged activation and
    mislocalization of cdk5.
  • Consequently, the p25 / cdk5 kinase
    hyperphosphorylates tau, disrupts the
    cytoskeleton, and promotes apoptosis of primary
    neurons.

37
Tau, calpains and apoptosis
  • preaggregated Aß induced the generation of a
    neurotoxic 17-kDa tau fragment
  • prevented by a calpain inhibitor
  • Prevented by anti-tau.

38
Apolipoprotein E4 (ApoE4)
  • Approximately 15 of the human population inherit
    an allele, apolipoprotein E4 (ApoE4) which can
    increase the risk for AD by approximately 3-fold
    .
  • The APO E gene comes in three flavors, the
    epsilon 2, epsilon 3 and epsilon 4 alleles.

39
Apolipoprotein E4 (ApoE4)
  • In healthy people, the frequency of the epsilon 4
    allele is 10 in AD patients, this frequency is
    increased to over 40.
  • The existence of one or two copies of the epsilon
    4 allele increases of the AD onset in a
    dose-dependant manner

40
Apolipoprotein E4 (ApoE4)
  • This allele increases cholesterol concentrations
    and may be responsible for augmenting the amount
    of Aß or decreasing its clearance .
  • the formation of myelin is dependent on
    cholesterol, it has been suggested that
    cholesterol may be partially responsible for the
    progression of AD

41
Statins for Alzheimer
  • Medications which inhibit 3-hydroxy-3-methylglutar
    yl- coenzyme A (HMG-CoA) reductase have been
    proven to reduce serum cholesterol, and low
    density lipoproteins (LDL)
  • lovastatin, simvastatin and cerivastatin cross
    BBB reduce the amount of Aß peptides by reducing
    cholesterol from the blood and/or the
    cerebrospinal fluid (CSF)

42
Anti-inflammatory
  • Inflammation is also occurring during the
    development of AD (Rogers et al. 1992 Akiyama et
    al. 2000).
  • senile plaques attracting activated microglia,
    reactive astrocytes, cytokines and complement
    components (Akiyama et al. 2000)
  • Reduction in the risk of AD associated with a
    chronic use of non-steroidal anti-inflammatory
    drugs (NSAID) ibuprofen, indomethacin ,but no
    other NSAID decrease the release of Aß

43
Treatment of behavioural signs
  • Behavioural signs, such as aggression,
    psychomotor agitation, and psychosis
    (hallucinations and delusions)
  • Atypical antipsychotic drugs

44
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.

45
  • Familial AD (rare) results from mutations in the
    genes for APP, or presenilin genes (involve in
    ?-secretases function) , both of which cause
    increased Aß formation.
  • Mutation in lipoprotein ApoE4 increase the risk
    of developing AD probably by interfering with Aß
    clearance
  • Neurofibrillary tangles comprise aggregates of a
    highly phosphorylated form of a normal neuronal
    protein (Tau). Hyperphosphorylated Tau and Aß act
    synergistically to cause neurodegeneration.

46
  • 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.

47
Clinical use of drugs in dementia
  • Acetylcholinesterase inhibitors and NMDA
    antagonists detectably improve cognitive
    impairment in clinical trials but have
    significant adverse effects and are of limited
    use clinically. They have not been shown to
    retard neurodegeneration.
  • Efficacy is monitored periodically in individual
    patients, and administration continued only if
    the drugs are believed to be working and their
    effect in slowing functional and behavioural
    deterioration is judged to outweigh adverse
    effects.
  • Acetylcholinesterase inhibitors Donepezil,
    galantamine, rivastigmine. Tacrine is also
    effective, but may cause liver damage. Unwanted
    cholinergic effects may be troublesome.
  • Used in mild to moderate Alzheimer's disease.
  • NMDA receptor antagonists For example, memantine
  • Used in moderate to severe Alzheimer's disease.

48
  • Certain anti-inflammatory drugs, and also
    clioquinol (a metal chelating agent), may retard
    neurodegeneration and are undergoing clinical
    evaluation.
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