Alzheimer's disease, Detailed pathophysiology and treatment methods of Alzheimer's disease with recent advances

1. ALZHEIMER’S DISEASE
BY
GURUBARATH M
M.PHARM (PHARMACOLOGY)
PSG College of Pharmacy
RECENT ADVANCES

2. ALZHEIMER’S DISEASE
Progressive neurodegenerative disease that leads to symptoms of Dementia
Poor memory
Difficulty learning
Make it really hard to
function independently
Caused by damage to brain cells By variety of diseases
(Alzheimer’s)Neurodegenerative
Particularly in cortex
Causes are not completely understood
DEMENTIA Set of symptoms
Characterized by
Neuronal cell dysfunction/death
Shrinkage of brain tissue
Progressive Cognitive, motor, behavioral impairment - Death
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3. ALZHEIMER’S DISEASE
Healthy brain Alzheimer’s brain
Cerebral cortex
(Language and information processing)
Narrowed Gyri
Widened Sulci
Hippocampus
(Important in forming memories)
Ventricle expansion
(Atrophy)
(Atrophy)
Extracellular
senile plaques
Intracellular
Neurofibrillary
Tangles
Degradation of Neurons
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PATHOPHYSIOLOGY

5. PATHOPHYSIOLOGY
Complex and entirely not understood
Currently few different hypothesis that try to explain the
cause of Alzheimer’s disease
Most popular one’s include,
Cholinergic hypothesis Possible cause of AD is the loss of central cholinergic
neurons and ensuing deficiency of acetylcholine
(Involved in memory and learning)
Amyloid hypothesis
Tau hypothesis
Accumulation of beta amyloid
proteins – Senile Plaques
Abnormal aggregation of Tau proteins – Neurofibrillary
Tangles
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6. PATHOPHYSIOLOGY
In Alzheimer's disease 10-15 years before appearance of symptoms,
2 main lesions form in the brain
SENILE PLAQUES Composed of Amyloid Beta protein
NEUROFIBRILLARY
TANGLES
Composed of Tau protein
How it is formed?
On the surface of neuron is a large protein called
Amyloid Precursor Protein (APP)
Normally it is sectioned by enzymes on the surface of
neuron and it frees a protein called Amyloid Beta.
It is then cleared in the body
In case of Alzheimer's, there is an imbalance. The amyloid
beta protein is no longer regulated.
The protein assemble to form insoluble flake called Senile Plaques
These Senile plaques are thought to induce Neuroinflammation
and disrupt communication between neurons June 2020PSG College of Pharmacy 6

7. PATHOPHYSIOLOGY
SENILE PLAQUES
Neural synaptic junction
Amyloid beta
monomers
Amyloid beta
oligomers
Aggregated
oligomers
Senile plaques
Neurotransmitter
Receptors
Vesicle
containing
Neurotransmitter
Axon terminal of
Presynaptic Neuron
Dendrite of
Post-synaptic neuron
Neural
communication
blocked !
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8. NEUROFIBRILLARY TANGLES
How it is formed?
PATHOPHYSIOLOGY
When a neuron communicates with another, a signal
goes from the body called Soma to Synapse
Soma
Synapse
Microtubules
Signal passes through the skeleton of neuron
composed of microtubules
These microtubules are stabilized by normal
Tau proteins
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9. Amyloid beta
Motor protein kinesin
Tau protein
Microtubule
highway
Stabilizes microtubules
NEUROFIBRILLARY TANGLES How it is formed?
Neurofibrillary tangle
Destabilized microtubules
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Motor protein kinesin

10. Extracellular Senile Plaques
Block neural junctions
Intracellular Tangles
Disrupt transport
Neurons become
dysfunctional and Die
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11. HOW DOES THESE LESIONS SPREAD?
Senile Plaques
Initially observed in the cortex, secondly in
Hippocampus then reach whole brain following
Centripetal movement
The progression does not correspond to the
symptoms of disease
Neurofibrillary Tangles
First develop in Hippocampus (center of memory
and learning), then reach whole brain following
Centrifugal movement
The process causes Atrophy (Global
dysfunction)
Progression of lesions corresponds with the
symptoms of disease
Symptoms begin with Memory
problems followed by problems of
language, recognition and incapacity to
form Gestures
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12. Enzyme ChAT
(Choline acetyl Transferase)
Soma
Synapse
ChAT
Cholinergic neuron
Vesicles containing
Neurotransmitter
Acetylcholine
produced by ChAT
Cerebral cortex
Hippocampus
ChAT travels in anterograde
to the axon terminal
Alzheimer’s Disease : Dysfunctional cholinergic neurons
Decreased Choline uptake
Decreased Ach release
Decreased ChAT
Decreased Nicotinic receptors
This reduction in ChAT is correlated with
the no. of Senile plaques and Disease
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13. Sporadic
Accounts for about 90-95% of cases
ALZHEIMER’S DISEASE - TYPES
Familial
Accounts for about 5-10% of cases
Late onset Early onset
Combination of genetic and
environmental risk factors
Risk increases with,
- affecting around
1% age=60-65
50% age<85
Gene
Contributing to an increased risk of AD is
e4 allele of Apolipoprotein E gene
(APOE-e4)
APOE e4 x 1 – Risk ↑
APOE e4 x 2 – Risk ↑↑
Helps breakdown of Beta
amyloid but e4 allele seems to
be less effective allele
Some Dominant gene was inherited – speeds up
the disease progression
Gene mutations
1st mutations in
PSEN-1 or PSEN-2 genes on chromosome 14 and
chromosome 1 respectively
These genes encode for Presenilin-1 or Presenilin-2
– both protein are subunits of δ secretase
Mutations in these PSEN-1 or PSEN-2 genes can
change the location where δ secretase chops APP
Down syndrome (Trisomy 21)
Extra copy of chromosome 21 (Contains the gene
responsible for producing APP)
Increased amounts of Amyloid plaques
CAUSE CAUSE
Age
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14. PATHOLOGICAL CASCADE OF
ALZHEIMER’S DISEASE
Amyloid precursor protein
(APP) cleavage
Increased Amyloid Beta
Senile Amyloid Plaques
Clinical symptoms
Neurodegeneration
Cholinergic Dysfunction
Tau Hyperphosphorylation
Neurofibrillary Tangles
Environmental Risk Factors
Sedentary lifestyle, High cholesterol,
High blood pressure and Diabetes
Pathogenic
Mutations
Inheritance of
APOE e4 allele
Mutations in
Presenilin Genes
Down syndrome
Might not be
detectable
Loss of motor
skills and
language Disoriented Death
BedriddenLong term
memory loss
Short term
memory loss
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15. DIAGNOSIS
Diagnosis of Alzheimer’s disease is tough
The only Definitive way to show a person had Alzheimer’s is
by performing a Brain biopsy (After Autopsy)
Clinician will make diagnosis after excluding other causes of
Dementia
To aid in the diagnosis of Alzheimer’s disease a Mini Mental
State Exam (MMSE) is given
This exam is divided into several groups of questions and
challenges that is graded out of thirty points
DISEASE PROGESSION
Symptoms expressed
Diagnosed
Loss of independence
Behavioral changes
Nursing home placement
MMSEScore
Disease Duration (years)
Mild stage Moderate stage Severe stage
Short term memory loss
Social withdrawal
Loss of sense of humor
Language deficits
Inability to solve problem
Loss of Motor skills
Depression/Aggression
Hostility
Mute
Incontinent
Bedridden
Death due to
Aspiration Pneumonia
Infection
Cardiac arrest
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16. Slow heartbeat, lack of appetite
and weight loss
TREATMENT
Current therapeutic options are limited to drugs that provide only
mild symptomatic benefit
Two classes
Cholinesterase inhibitors
NMDA receptor antagonist
Cholinesterase inhibitors
Normal conditions
Cholinergic neurons in brain –
Synthesis Acetylcholine from Acetyl
CoA and Choline
Upon impulse Acetylcholine is
released into synaptic cleft
Two enzymes AChE and BuChE
breakdown Acetylcholine into Acetate
and Choline
Acetylcholine
Acetylcholinesterase
Butyrylcholinesterase
Alzheimer’s Enhanced breakdown of AcetylcholineCholinesterase inhibitors Work simply by inhibiting ChE enzymes from
breaking down Ach, thereby increasing both
level and duration of action of ACh
X
X Commonly prescribed ChE
inhibitors;
Donapezil
Rivastigmine
Galantamine
SIDE EFFECTS
Mild
Serious
Nausea, vomiting, diarrhea
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17. TREATMENT
NMDA receptor antagonist
NMDA receptors Belong to family of Ionotropic glutamate receptors,
which mediate most of the excitatory synaptic
transmission in brain
Play important role in
learning and memory
Beta amyloid
Beta amyloid proteins in Alzheimer
patient’s brain cause accumulation
of Glutamate by inhibiting Uptake
Also triggers Glutamate release
from Glial cells
Microglia
Binding of glutamate to NMDA
receptors results in an influx of
extracellular calcium
Causing membrane excitability
and synaptic transmission
Ca2+
Glutamine levels becomes
abnormally elevated –
overstimulation of NMDA
receptors
Alzheimer’s
Leads to excessive influx of
calcium and causing the
cell to rupture and die
NMDA receptor antagonist such as
Memantine cause blockage of receptors
thus limiting calcium influx into the
neuron
X
SIDE EFFECTS
Diarrhea
Headache
Insomnia
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RECENT ADVANCEMENTS

19. RECENT ADVANCEMENTS
DIAGNOSIS
Research has changed AD diagnosis it provides;
Protein analysis of cerebra spinal fluid
Biomarkers of Alzheimer’s disease
Increased confidence and Ability to diagnose earlier
Magnetic resonance imaging measures of brain volume
(Diffusion tensor imaging)
Molecular neuroimaging (PET scans)
 Last few years have yielded immense insights into the pathogenesis of AD
 Microscopic structural changes are now understood in the context of what
is happening pathologically on a molecular level
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20. RECENT ADVANCEMENTS
TREATMENT
Currently available drugs provide temporary relief of symptoms – they do not stop
or slowdown the underlying neurodegenerative process
New experimental drugs are developed to target the root
causes of the disease
One of the promising targets for future drugs is Beta amyloid
Researches are invested on agents that may prevent Aβ
plaques by targeting β-secretase and δ-secretase
β-secretase
δ-secretase
Researchers also been testing Antibodies that bind to
Beta amyloid and enhance its clearance from brain
Another major target for future therapies is Tau protein
Antibodies capable of binding and clearing pathological Tau
proteins are currently being developed and tested
Another area involves compounds that prevent Tau aggregation
or dissolve existing aggregates and Inhibit microtubule
assembly
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21. RECENT ADVANCEMENTS
TREATMENT :
FOCUSED ON TARGETING Aβ AND TAU
Aβ TARGETING STRATEGIES
APP can be also be processed by α-secretase within Aβ
sequence and generate soluble neurotrophic sAPPα.
The pathological accumulation of Aβ in brain leads to oxidative
stress, neuronal dysfunction and clinical symptoms of AD
Secondary prevention of AD can be made by:
Decreasing production of Aβ
Stimulation of clearance of Aβ formed
Prevention of aggregation of Aβ into amyloid plaques
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22. RECENT ADVANCEMENTS
TREATMENT :
FOCUSED ON TARGETING Aβ
β-SECRETASE INHIBITORS
The therapeutic potential of β-secretase (also named β-site APP
cleaving enzyme, BACE1) inhibitor has been suggested by
several studies.
Lateral ventricles injection of BACE inhibitor led to a significant
dose- and time-dependent lowering of brain Aβ40 and Aβ42, a
robust decreased sAPPβ and an increased sAPPα secretion.
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23. RECENT ADVANCEMENTS
TREATMENT :
FOCUSED ON TARGETING Aβ
γ-SECRETASE INHIBITORS/MODULATORS
Treatment of AD mice/rats with γ-secretase inhibitors
DAPT resulted in decreased Aβ levels in plasma and
cerebrospinal fluid
Notch related side effects of γ-secretase inhibition (e.g. severe
gastrointestinal and hemopoietic side effects,
neurodegeneration) have been hampering the development of
clinically useful γ-secretase inhibitors so far.
The drug development is now focusing on the development
of γ-secretase modulators, with the purpose of shifting the
γ-secretase cutting point to produce shorter, non-toxic Aβ
fragments
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24. RECENT ADVANCEMENTS
TREATMENT :
FOCUSED ON TARGETING Aβ
α-SECRETASE ACTIVATORS/MODULATORS
Upregulation of α-secretase activity may decrease the amount
of APP available for β-secretase, and thus decrease Aβ
secretion and have therapeutic potential
Stimulating α-secretase through several pathways may have
therapeutic potential and the work is going on, but no clinical
data available at present.
Aβ-AGGREGATION INHIBITORS
The neurotoxic effect of Aβ has been documented on
numerous occasions and thus decreasing its neurotoxicity or
inhibiting its aggregation may have therapeutic potentials
The first drug was a β-sheet breaker iAβ5p, which showed that
intrahippocampal injection of it resulted in improved spatial
memory and decreased amyloid plaque deposits.
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25. RECENT ADVANCEMENTS
TREATMENT :
FOCUSED ON TARGETING Aβ
M1 muscarinic agonists
M1 muscarinic receptors play a role in an apparent link-
age of three major hallmarks of AD:
Activation of M1 mAChRs with these agonists leads to
enhanced secretion of sAPPα, (via α-secretase activation),
to decreased Aβ (via γ-secretase inhibition), and the inhibition
of Aβ- and/or oxidative stress-induced cell death
 Aβ peptide;
 tau hyperphosphorylation
 loss of cholinergic function conductive to cognitive impairments.
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26. RECENT ADVANCEMENTS
TREATMENT :
FOCUSED ON TARGETING Aβ
Aβ-DEGRADING ENZYMES
Recent studies have indicated that Aβ peptide could be degraded by a kind
of protease called Aβ degrading enzyme, rather than being cleared from
the vascular system by the so-called “vascular pathway”.
The following proteinases have the abilities of degrading Aβ peptide:
 Neprilysin (NEP)
 Insulin degrading enzyme (IDE)
 Plasmin
 endothelin converting enzyme (ECE) 1 and 2 and
 angiotensin-converting enzyme (ACE).
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27. RECENT ADVANCEMENTS
TREATMENT :
FOCUSED ON TARGETING Aβ
APOLIPOPROTEIN E (APOE) PROMOTES Aβ CLEARANCE
Recent studies have indicated that it was the decreased clearance/degradation
rather than increased production of Aβ account for its deposition in sporadic
AD
The nuclear receptor-mediated, ApoE-directed therapeutics thus can
decrease brain Aβ level and have disease-modifying potentials in AD
prevention
Bexarotene is a nuclear receptor modulator and ApoE activator,
whether it is effective in AD prevention needs to be explored
clinically
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28. RECENT ADVANCEMENTS
TREATMENT :
BASED ON TAU PATHOLOGY
PREVENTION OF PHOSPHORYLATION OF TAU
Tau phosphorylation increases dramatically in AD, suggesting Tau kinase
inhibitors could be used as an anti-AD treatment
Inhibitors of Tau aggregation independent of phosphorylation have
been found and tested in cell cultures
Recent studies using cell models have demonstrated that certain
drug inhibitors are able to prevent tau protein aggregation and even
dissolve the developed aggregates, which include
PREVENTION OF THE AGGREGATION OF TAU
Phenothiazines, anthraquinones, polyphenols, thiacarbocyanine
dyes, N-phenylamines, thiazolyl-hydrazides, rhodanines,
quinoxalines, amino thienopyridazines.
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29. RECENT ADVANCEMENTS
TREATMENT :
BASED ON TAU PATHOLOGY
PREVENT THE MISFOLDING OF TAU
In addition to tau aggregation, the misfolding of hyper-phosphorylated tau
proteins has also been suggested to contribute to the pathology of AD.
Increasing the activation of molecular chaperones might prevent the
misfolding of tau, which would then reduce the development of NFTs.
Additional research is required to determine whether targeting tau
chaperones would be able to produce significant benefit in humans.
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30. RECENT ADVANCEMENTS
TREATMENT
CELL TRANSPLANTATION AND GENE THERAPY
In AD rat model, transplantation of cholinergic-rich tissue or peripheral
cholinergic neurons ameliorates abnormal behavior and cognitive function.
But no clinical trials in AD patients have been initiated with this
method
NON PHARMACEUTICAL TREATMENT
The Advanced Cognitive Training for Independent and Vital Elderly
(ACTIVE) study examined the effects of cognitive training in elderly individuals
randomly assigned to one of three cognitive training programs:
Reasoning, Speed of processing, and Memory training
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31. RECENT ADVANCEMENTS
OTHER PHARMACOLOGICAL THERAPIES IN
AD CLINICAL TRAILS
DOCOSA-HEXAENOIC ACID (DHA)
Epidemiological studies suggest that increased intake of the omega-3(n-3)
polyunsaturated fatty acid DHA is associated with a reduced risk for AD
Positive effects were observed in a small group of patients with very
mild AD
CLIOQUINOL
Metal chelation using clioquinol has been reported in a pilot study with 36 patients
with AD to reduce the rate of cognitive loss in a double-blind, placebo-controlled,
phase 2 clinical trial.
Clioquinol’s effect in this preliminary study is due to its ability to
chelate zinc and copper associated with amyloid plaques.
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32. RECENT ADVANCEMENTS
OTHER PHARMACOLOGICAL THERAPIES IN
AD CLINICAL TRAILS
RESVERATROL
Resveratrol modulates multiple mechanisms of AD pathology.
It has been recently suggested that Resveratrol can be effective in
slowing down AD development.
As reported in many biochemical studies, resveratrol seems to exert
its neuroprotective role through
 Inhibition of Aβ aggregation
 By scavenging oxidants
 Exerting anti-inflammatory activities
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33. RECENT ADVANCEMENTS
TREATMENT
Current therapies for patients with AD may ease symptoms by providing
temporary improvement and reducing the rate of cognitive decline.
Given the wide array of available molecular targets and the rapid
progress toward identifying potential therapeutic compounds,
- The development of interventions that substantially delay the onset
or modify the progression of AD can be anticipated.
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34. REFERENCE
Recent progress in Alzheimer’s Disease Research, Part 3 : Diagnosis and
Treatment; Francis T Hane, Morgan Robinson, Brenda Y Lee, Mitchell S Albert.
Current Advances in the Treatment of Alzheimer’s Disease : Focused on
considerations targeting Aβ and Tau; Yang Hong-Qi, Sun Zhi-Kun, Chen Sheng-Di.
Open.osmosis.org/Alzheimer’s disease
Mechanisms and secrets of Alzheimer’s disease: exploring the brain;
Internationale Stichting Alzheimer Onderzoek, Alzheimer Forschung Initiative
www.alzheimer-research.eu
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