B2-Group 7

Ilaya, Daniel
Isman, Aina
Isyasa, Janine Ann
Jamandre, Reinhard
Ethel
Jones
 Imbalances of hormones/ neurotransmitters
involved
 Association of lipoproteins and cholesterol,
inflammation and immune response, metal
toxicity, free radicals and smoking
 Treatment/ management and rationale
behind each drug
• Premature aging of the
brain in which
progressive and fatal
neurodegenerative
condition occurs
• Most common form of
dementia
• Alois Alzheimer -
German physician
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Caused by build-up of:
• amyloid plaques 
• tau-containing neurofibrillary tangles
• result in the death of brain cells
 AD follow a characteristic pattern:
Memory impairment language and
visiospatial deficits

 Early stage:
 Unrecognized memory loss
 Memory loss

 Dramatic personality
changes
 Disorientation

 Declining physical
coordination
 Inability to care for
themselves
 Victims are bedridden

 Lost urinary and bowel

control
 Suffer epileptic attacks

 Death is due to:

 Pneumonia
 Bedsores
 Urinary tract infection
• Familial Alzheimer’s Disease (FAD)
• Genetically inherited AD

• Sporadic Alzheimer’s Disease (SAD)

• Majority

• Person w/ parent or sibling with AD > person

w/o family history of AD

9
• If more than one close relative has been
affected = risk more

• FAD’s early-onset occurs at 30-60

• SAD occurs at 60+

• Mutation in chromosomes 1, 14, and 21 can cause

early onset FAD
 Chromosome 21 (the chromosome triplicates
in Down Syndorme)
 an abnormal Amyloid Precursor Protein (APP)

 Chromosome 14
 abnormal protein Presenilin 1 (PS1)

 Chromosome 1
 abnormal protein Presenilin 2 (PS2)

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 PS1 & PS2 influences gamma-secretase enzyme
causes more Aß42 peptide formation

 Chromosome 19 considered as late onset SAD; having

APOE4 gene

 Acts as a risk factor

 Individuals who inherited these mutated genes

will almost unavoidably develop onset AD
CHROMOSOME PROTEIN TYPE OF AD PRODUCT
 Individuals with Down Syndrome who surviedIncreasing
at age
1 Presenilin 2 (PS2) FAD; Early onset
50 frequently develop Alzheimer’s Disease.production of Aß 42

14 Presenilin 1(PS1) FAD; Early onset Increasing

production of Aß42

21 Amyloid Precursor FAD; Early onset Increasing

Protein (APP) production of Aß42

19 Apolipoprotein E SAD; Late onset Causing AD to

gene (APOE4) develop several
years sooner.
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 1992- John Hardy and Gerald Higgis

 An alteration in the expression or processing

of the amyloid precursor protein (APP)

 Accumulation of beta-amyloid
 APP
 Integral membrane protein expressed in many
tissues and concentrated in the synapses of
neurons.
 Primary function is unknown
 implicated as a regulator of synapse formation
and neural plasticity
 APP is cleaved by either β- secretase or α-
secretase to produce small non- toxic products

 Cleavage of β- secretase product by γ-

secretase in either the toxic Aβ42 (containing
42 amino acids or the non- toxic Aβ40 peptide

 Cleavage of the α- secretase product by γ-

secretase produces the non- toxic P3 peptide
 Amyloid beta 42 also produces tiny fibers, or
fibrils. When they stick together they form
amyloid plaque.

 α,γ cleavage - extracellularly

 β,γ cleavage - endosomal-lysosomal
compartment
- intracellularly
- damaging when transported
 Aß42
 42 amino acid amyloid beta peptide
 more hydrophobic & sticky
 aggregates more readily

 Aß42 - concentrated amyloid-beta in

neuritic plaques
 Aß40 - concentrated in cerebrovascular
plaques
 Astrocytes
 more numerous in AD
 activated to produce prostaglandin/arachidonic
acid mediated inflammation
 Microglia
 Activation damaging free radicals

Results to: DEATH OF NEURONS

 Neurons in the brain are supported & nurtured
by glial cells
 Macroglia or microglia

 Microglia = macrophages
 Normal microglia = in number
 Multiply in response to injury & infection
 Concentrated around amyloid plaques
 With reactive astrocytes
 Amyloid-beta activation of microglia will
produce inflammatory cytokines:
 InterLeukin-1ß (IL-1ß)
 Tumor Necrosis Factor alpha (TNF−α)

 Amyloid-beta also activates the transcription

factor NF−κB which increases cytokine
production by neurons as well as by microglia
 Cytokine involved in systemic inflammation
and is a member of a group of cytokines that
stimulate the acute phase reaction

 Regulation of immune cells

 Induce apoptosis, inflammation, viral

replication
 Nuclear factor kappa-light-chain-enhancer of
activated B cells
 Controls the transcription of DNA
 involved in responses to stimuli such as:
 stress, cytokines, free radicals, ultraviolet
irradiation, oxidized LDL, and bacterial or viral
antigens
 plays a key role in regulating the immune
response to infection
 Enzymes induced by microglia:
 Nitric oxide synthetase
▪ generate nitric oxide leading to Peroxynitrite and
oxidative stress

 IL-1ß further aggravates immune response by

promoting:
 more APP synthesis
 production of more Aß-binding proteins by
astrocytes
 Results from elevated nitric oxide synthetase
induced by inflammation & excitotoxicity

 proton leak across inner mitochondrial

membrane
 inhibits mitochondrial enzymes
 inhibits antioxidant enzymes
 free-radical damage
 Over-expression of interleukin-1 near amyloid
plaques may promote the phosphorylation of
tau protein

 Formation of NeuroFibrillary Tangles (NFTs)

and neuron death 
 Tau
 maintains the structural integrity of microtubules
 normally binds to and regulates microtubule
polymerization

 Microtubules
 Where substances for nutrient & cell-regulation
are transported along
 Phosphorylated tau proteins bind to each
other

 Tie themselves in "knots"

 paired helical filaments -- 2 threads of tau wound
around each other

 Neurons full of NFTs rather than functional

microtubules soon die
 In Alzheimer’s disease:
 Proteins become hyperphosphorylated and
aggregate

 microtubule depolymerization along with the

degeneration of a cell’s axons and dendrites
 cerebral cortical levels of
neurotransmitters
 Acetylcholine
 Choline acetyltransferase
 Nicotinic cholinergic receptors
 Responsible for memory recall
 How fast brain process information
 Reduction of norepinephrine in brainstem
nuclei
 APOlipoproteins (APOs)
 protein portion of the lipoproteins
(LDL,HDL,VLDL,etc) that transport cholesterol

 Like the other apolipoproteins,

APOlipoprotein E (APOE) is synthesized in
the liver
• APOE acts as a binding site for LDL receptors
• allow lipids/cholesterol to be assimilated into cells

• APOE mobilization of cholesterol in the

Central Nervous System (CNS) is apparently of
particular importance for synapse plasticity &
repair of damaged neurons
 Alzheimer's Disease is characterized by
plaques consisting of the peptide beta-
amyloid
 Apolipoprotein E enhances proteolytic break-
down of this peptide, both within and between
cells.
 FORMS
APOE2 •lower Has cysteine binds & removes protects cultured
cholesterol levels residue that amyloid -beta neurons from
protects against amyloid-beta
• lower AD risk HNE
neurotoxicity

APOE3 Has cysteine binds & removes APOE3 gives

residue that amyloid-beta intermediate
protects against protection 
HNE
neurotoxicity

APOE4 Higher Has no cysteine does not bind APOE4 gives the
residues and is amyloid-beta at least protection
plasma therefore not all 
cholesterol very protective
and an even against covalent
modification of
higher risk of proteins by HNE
AD
 M2 muscarinic and nicotinic receptors are in
patients with AD

 Nicotine inhibits the formation of amyloid

plaque
 nicotine receptors and senile plaques are
not surprising among autopsies of smokers

 Nicotine administration into rat hippocampus

produces lasting elevation of Nerve Growth
Factor (NGF)
 enhancing acetylcholine production & release
[BIOLOGICAL PSYCHIATRY 49:185-193 (2001)]
 Studies of AD patients have shown beneficial
effects of nicotine administration

 Nonetheless, a mouse model has shown a

worsening of tau protein pathology (NFTs)
due to nicotine administration
 Aluminum concentration is elevated in NFTs
& amyloid plaques
 effect of AD rather than a cause
 Mercury
 can bind to tubulin
▪ the primary protein constituent of microtubules
▪ interfere with microtubule assembly

 Zinc & selenium may protect against mercury

neurotoxicity
 Zinc, Copper, Iron
 enriched in amyloid-beta plaques
 Copper & Iron
 generate hydrogen peroxide = oxidative damage 
 Zinc binds to and precipitates amyloid-beta
 may have a protective effect
 displacing copper & iron enriched in amyloid-beta
plaques in AD
 zinc can initiate plaque formation by its
ability to bind to Aß under non-acidic
conditions and by creating the inflammation
which leads to acidity. Under acidic
conditions -- such as exists in inflammed
tissue -- copper displaces zinc 
 Copper enhances ß-sheet formation of
amyloid-beta fibrils and this enhancement is
potentiated by APOE4
 Membranes containing oxidatively damaged
phospholipids also promote amyloid ß-sheet
formation
 In its free state amyloid-beta has antioxidant
properties which have beneficial effects for
neurons.
 But amyloid-beta aggregation by acidic
conditions and by copper, iron, zinc & aluminum
results in the highly toxic & pro-oxidant ß-
sheets.
 The binding is particularly strong for copper.
Copper binds more strongly to Aß42 than to Aß40
and copper is a greater catalyst of free radical
formation than are the other metals
 Cu2+ bound to free Aß42 is reduced by O2 to
produce H2O2
 Thus, copper, and to a lesser extent iron,
appear to be the most serious metal toxicities
in AD.
The use of tacrine is no longer
recommended due to
hepatotoxicity
Generic Brand Approved For Side Effects

donepezil Aricept All stages Nausea, vomiting, loss of

appetite and increased
frequency of bowel
movements.

galantamine Razadyne Mild to moderate Nausea, vomiting, loss of

appetite and increased
frequency of bowel
movements.

memantine Namenda Moderate to severe Headache, constipation,

confusion and dizziness.

rivastigmine Exelon Mild to moderate Nausea, vomiting, loss of

appetite and increased
frequency of bowel
movements.

tacrine Cognex Mild to moderate Possible liver damage,

nausea, and vomiting.
The use of tacrine is no longer
recommended due to
hepatotoxicity
○ Acetylcholinesterase (AchE) terminates cholinergic nerve
transmission

○AchE is found both on the post-synaptic membrane of

cholinergic synapses and in other tissues like the RBC
○ Ach binds to AchE and is hydrolyzed to
acetate and choline

○This inactivates the Ach and the nerve

impulse is halted

○ AchE inhibitors (ex. rivastigmine) prevent the

hydrolysis of Ach, which increases the
concentration of Ach in the synaptic cleft
Generic Brand Approved For Side Effects

donepezil Aricep All stages Nausea, vomiting,

loss of appetite and
increased frequency
of bowel movements.

galantamine Razadyne Mild to moderate Nausea, vomiting,

loss of appetite and
increased frequency
of bowel movements.

memantine Namenda Moderate to severe Headache,

constipation,
confusion and
dizziness.
rivastigmine Exelon Mild to moderate Nausea, vomiting,
loss of appetite and
increased frequency
of bowel movements.

tacrine Cognex Mild to moderate Possible liver

damage, nausea,
and vomiting.
 Regular Exercise
 Eat a brain healthy diet
 Build brain reserves
 Sleep well
 Inhibition of cholinesterase
Resulting effect: INCREASE cerebral levels of
ACETYLCHOLINE

 Memantine appears to act by blocking

overexcited N-methyl-D-aspartate (NMDA)
 also known as Glutamatergic channels
 These channels manifests neuronal excitotoxicity
 Resulting effects:
 decreases cognitive deterioration in patients with
moderate to severe AD and is not approved for
mild AD

 Memantine inhibits the prolonged influxed of

Calcium ions to the NMDA receptors
 A 72-yr-old woman who lived on her own was
found wandering around her neighbourhood
at 2am. Her husband died 3 years previously
and her one son lived some distance away.
The lady was confused and taken to the
hospital. The son was notified and came
immediately to see his mother.
 He was not able to come at the time of
admission to give a clear history. He said that
her mother had been diagnosed by a
neurologist as having and early AD, but had
refused to go into nursing home. She had
some help during the day, and had not
previously wandered out or her home..
 Sometimes a lady friend visited and spent the
night out of her home. In fact, she appeared
relatively normal prior to the present situation,
as her son spoke to her on the phone every day
of the week.
 However, her short-term memory had become
worse in recent months, and he is concerned
about it. She was on medication ( donezepil ) for
AD. Otherwise she had no significant medical
history.
 She was kept in the hospital for a couple of
days, during which time her family doctor
and her neurologist were consulted.
 "THE HARDEST PART
ABOUT HAVING
ALZHEIMER'S DISEASE
IS NOT FORGETTING
HOW TO DO THINGS,
IT'S FORGETTING WHO
YOU ARE."
 Pictures of tau and amyloid, mech of drugs
and why use them
 Acidosis caused by Inflammation
 Role of copper in free radical formation
 How copper is acquired in the body
 Yung ibang slides, ttnggalin ko pa, guide ko
lang for the diagrams
