Pharmacotherapy of Alzheimer's Disease
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Transcript of Pharmacotherapy of Alzheimer's Disease
Pharmacotherapy of Alzheimer’s Disease
Pharmacotherapy of Alzheimer's disease
Definition:Alzheimer's disease: A primary degenerative
cerebral disease of unknown etiology with characteristic neuropathological & neurochemical features
Alzheimer’s disease - Most common type of dementia accounts for 60 to 80 % of cases
Dementia: A clinical syndrome of loss or decline in memory, intellectual deterioration & other cognitive abilities with changes in personality & behavioural abnormalities10th February 2009 2
Pharmacotherapy of Alzheimer's disease
Alzheimer’s disease1st described by German psychiatrist Alois
Alzheimer in 1906
Dementia in Alzheimer's disease with early onset: Onset before the age of 65 with a relatively rapid deteriorating course & with marked multiple disorders of higher cortical functions
Dementia in Alzheimer's disease with late onset: Onset after the age of 65 usually in late 70s or thereafter with a slow progression & with memory impairment as principal feature
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Pharmacotherapy of Alzheimer's disease
PrevalencePrevalence of dementia in India & South Asia
is 1.9% in those ≥60 years with an annual
incidence of 4.3/1000
The prevalence is estimated to reach 3.6 million by 2020 and 7.5 million by 2040 in this region
The rate of increase was estimated to be 3-4
times higher in developing countries than in
developed countries10th February 2009 4
Pharmacotherapy of Alzheimer's disease
Symptoms of ADGradually worsening difficulty in
remembering new information Confusion, disorganized thinking,
impaired judgment, trouble expressing themselves
Disorientation to time, space & location
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Pharmacotherapy of Alzheimer's disease
Diagnostic criteriaMultiple cognitive deficits manifested by memory
impairment and one or more of aphasia, apraxia, agnosia or disturbance in executive functioning
Significant impairment in social or occupational functioning
Gradual onset and continuing cognitive decline
Symptoms not due to neurologic, systemic or substance abuse conditions known to cause dementia
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Pharmacotherapy of Alzheimer's disease
EtiologyAdvancing Age
Female sex
Family history
Trauma
Education
Environmental factors: Aluminum, Mercury, Viruses
Vascular diseases: Stroke10th February 2009 7
Pharmacotherapy of Alzheimer's disease
Genetic factors:
APP gene present on chr. 21
Adults with trisomy 21 develop typical
neuropathologic hallmarks of AD if they survive
beyond age 40
Investigations of multigenerational FAD led to
discovery of 2 additional AD genes termed as
preseninlins
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Cont.
Pharmacotherapy of Alzheimer's disease
PresenilinsPresenilin-1 on chr. 14 involved in cleavage of APP at
γ-secretase site
Mutations of this gene are more common than PS-2 & leads to early onset, shorter & rapidly progressive course
Presenilin-2 on chr. 1 encodes protein called STM2
Mutations of Presenilins rarely involved in late onset of Disease
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Cont.
Pharmacotherapy of Alzheimer's disease
Apo-ε gene Apo-ε gene on Chr. 19 responsible for late onset
familial & sporadic forms of AD
Its involved in cholesterol transport and has 3 alleles:
2, 3 & 4
Apo-ε4 has strong association with AD
Apo-ε4: Single most important biomarker associated with risk of AD
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Cont.
Pharmacotherapy of Alzheimer's disease
Neurochemistry of AD
Direct analysis of neurotransmitter content in cerebral cortex of AD patients shows a reduction of many transmitter substances that parallels neuronal loss
A striking & disproportionate deficiency of ACh due to atrophy & degeneration of subcortical cholinergic neurons particularly those in basal forebrain is seen
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Pharmacotherapy of Alzheimer's disease
PathogenesisAmyloid precursor protein (APP) is a type-I
transmembrane glycoprotein
Function of APP is still unclear & believed to be important during development of CNS & in response to stress or injury
APP undergoes proteolytic processing through physiologic i.e. non-amyloidogenic or amyloidogenic pathway
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10th February 2009 Pharmacotherapy of Alzheimer's disease 13
Pharmacotherapy of Alzheimer's disease
During physiologic pathway membrane bound enzyme α-secretase cleaves APP within its Aβ domain resulting in extracellular secretion of soluble APP-α (sAPP-α) & production of a short, membrane-bound COOH-terminal fragment (CTF), α-CTF or C83
Subsequent γ-secretase cleavage of C83 results in the secretion of a peptide termed p3 out of cell & release of the APP intracellular domain (AICD) into the cytoplasm
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Contd.
Pharmacotherapy of Alzheimer's disease10th February 2009 15
Pharmacotherapy of Alzheimer's disease
The amyloidogenic pathway is initiated when β-secretase cleaves APP at N-terminal part of Aβ domain
This cleavage leads to the extracellular release of sAPPβ, while β-CTF or C99 fragment remains membrane bound
Sequential γ-secretase cleavage of C99 allows shedding of AICD & secretion of Aβ into the lumen or extracellular space which aggregates to form amyloid plaques
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Contd.
Pharmacotherapy of Alzheimer's disease
Tau is a normal constituent of neurons associated with intracellular microtubules
In AD it becomes abnormally phosphorylated & deposited intracellularly as paired helical filaments
When the cells die, these filaments aggregate as extracellular neurofibrillary tangles
Addition of fibrillar Aβ to mature hippocampal neurons results in progressive neuritic degeneration accompanied by enhanced phosphorylation of adult τ-isoforms
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Contd.
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Pharmacotherapy of Alzheimer's disease
Pathological features
Brain shrinkage & localised loss of neurons, mainly in the hippocampus & basal forebrain
Loss of cholinergic neurons in the hippocampus & frontal cortex
Diffuse atrophy of cerebral cortex & enlargement of ventricular system
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Pharmacotherapy of Alzheimer's disease
Gross Appearance
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Pharmacotherapy of Alzheimer's disease
Microscopic Features
Extracellular amyloid plaques consisting of β amyloid protein (Aβ)
Intraneuronal neurofibrillary tangles comprising of filaments of phosphorylated form of a microtubule-associated protein (Tau)
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Hallmark of AD:
Pharmacotherapy of Alzheimer's disease
Microscopic features
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Pharmacotherapy of Alzheimer's disease
Current Pharmacotherapy
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Pharmacotherapy of Alzheimer's disease
The main goals of treatment
Symptomatic improvement, consist of enhanced cognition, more autonomy & improvement in neuropsychiatric & behavioural dysfunction
Disease modification with slowing or arrest of symptom progression of the dementing process
Primary prevention of disease by intervention in key pathogenic mechanisms at a pre-symptomatic stage
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Pharmacotherapy of Alzheimer's disease
Current treatment
Acetylcholinesterase inhibitors (AChEIs):
Tacrine, Donepezil, Galantamine, Rivastigmine &
Huperzine A
Non-competitive N-methyl-D-aspartate (NMDA)
receptor antagonist:
Memantine, Dimebolin
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Pharmacotherapy of Alzheimer's disease
Acetylcholinesterase inhibitors
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AChEI
Pharmacotherapy of Alzheimer's disease
Contd.Mechanism of action: The AChEIs act by
preventing the enzymatic degradation of the neurotransmitter acetylcholine (ACh) resulting in increased ACh concentrations in the synaptic cleft & enhanced cholinergic transmission
AChEIs may be divided into 3 groups: Noncovalent or “reversible” inhibitors, carbamoylating inhibitors & organophosphorus compounds
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1st AChEI approved by FDA for treatment of AD was Tacrine which is a reversible inhibitor & no longer used now due to hepatotoxicity
Major side effects: GI symptoms (Nausea, Diarrhea, Cramps), altered sleep, bradycardia & muscle cramps
Caution when using in people with cardiac conduction conditions such as symptomatic bradycardia, or with a history of falls or syncope
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Pharmacotherapy of Alzheimer's disease
RivastigmineReversible Carbamate Inhibitor
Rivastigmine tartrate: Oral: approved for mild & moderate AD only
It has a recently FDA-approved Transdermal patch that has been shown to eliminate GI side effects
Rivastigmine can be safely given to patients not tolerating or not responding to donepezil
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Pharmacotherapy of Alzheimer's disease
It is a reversible inhibitor bind with higher affinity to the active center
It is more hydrophobic & has longer duration of action
Readily cross blood–brain barrier to inhibit AChE in the CNS
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Donepezil
Pharmacotherapy of Alzheimer's disease
Intranasal galantamine achieved therapeutically relevent drug levels exceeding that of oral dosing & avoided GI side effects
Huperzine A is a natural AChEI derived from the Chinese herb Huperzia serrata, also acts as a NMDA receptor antagonist
It has antioxidant and neuroprotective properties that suggests its usefulness as a disease-modifying treatment for AD
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Contd.
Pharmacotherapy of Alzheimer's disease
NMDA receptor antagonist
Acts by blocking overexcited NMDA receptors which blocks entry of Ca++ thereby decreasing glutamate release & inhibiting processes which led to neurotoxicity
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Pharmacotherapy of Alzheimer's disease
Memantine
Mechanism of action: Voltage dependent, low-moderate affinity, uncompetitive NMDA receptor antagonism with fast blocking/unblocking kinetics
Fast on/off kinetics & low-moderate affinity blocks effect of excessive glutamate preserving physiologic activation of NMDA receptors required for learning & memory
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Pharmacotherapy of Alzheimer's disease
It also inhibits & reverses protein phosphatase(PP)-2A inhibition-induced abnormal hyperphosphorylation & accumulation of tau
Adverse effects are mild & reversible and may include headache or dizziness
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Cont.
Pharmacotherapy of Alzheimer's disease
DimebolinAn antihistamine drug
Multiple mechanisms of action:
Blocks the action of neurotoxic Aβ & inhibits L-type calcium channels
Modulates the action of AMPA and NMDA glutamate receptors
Exert a neuroprotective effect by blocking a novel target that involves mitochondrial pores
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Pharmacotherapy of Alzheimer's disease
Guidelines for Alzheimer’s disease management
California Workgroup on Guidelines for Alzheimer’s Disease Management has an update report in 2008
This report updates & expands the Guidelines for Alzheimer’s Disease Management (California Workgroup on Guidelines for Alzheimer’s Disease Management, 2002)
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Pharmacotherapy of Alzheimer's disease
It has the following recommendations:
Assessment Monitor Changes
Reassess Frequently
Identify Support
Identify Culture & Values
Assess Capacity
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Pharmacotherapy of Alzheimer's disease
Treatment Develop Treatment Plan
Treat Behavioural Symptoms
Non-Pharmacological Treatment First
Treat Co-Morbid Conditions
Provide End-of-Life Care
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Pharmacotherapy of Alzheimer's disease
Patient & family education & supportIntegrate Medical Care & Support
Discuss Diagnosis & Treatment
Involve Early-Stage Patients
Discuss Stages
Discuss End-of-Life Decisions
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Pharmacotherapy of Alzheimer's disease
Legal considerationsPlanning
Capacity Evaluations
Elder Abuse
Driving
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Pharmacotherapy of Alzheimer's disease10th February 2009 42
Pharmacotherapy of Alzheimer's disease10th February 2009 43
Pharmacotherapy of Alzheimer's disease
NSAIDs & ADPast studies found patients who reported
higher use of NSAIDs were less likely to develop AD compared to patients with less frequent NSAID use
These findings suggested that NSAIDs may have neuroprotective properties against development of AD
Recent double blind, placebo controlled trials have failed to demonstrate any therapeutic benefit in the development of AD
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Pharmacotherapy of Alzheimer's disease
Statins in ADStatins inhibit β-secretase & activate α-
secretase thereby decreasing Aβ load
Reduce the risk of dementia & cognitive impairment by modifying the vascular risk factors that have been implicated in both vascular dementia & Alzheimer’s disease
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Pharmacotherapy of Alzheimer's disease
Antipsychotics use in ADAdverse effects offset advantages in the efficacy of
atypical antipsychotic drugs for the treatment of psychosis, aggression, or agitation in AD patients
REGULATORY ALERT June 17, 2008: The U.S. FDA notified that both conventional & atypical antipsychotics are associated with an increased risk of mortality in elderly patients treated for dementia-related psychosis
Prescribing information for all antipsychotic drugs will now include information about the increased risk of death in the BOXED WARNING & WARNING sections
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Pharmacotherapy of Alzheimer's disease10th February 2009 47
Novel targets
Pharmacotherapy of Alzheimer's disease
Strategies targeting τ-protein
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Pharmacotherapy of Alzheimer's disease
1. Modulators of τ-kinases or phosphatases An imbalance in activity between kinases &
phosphatases results in abnormal phosphorylation of microtubule-associated τ-protein
Major kinases involved in this process are glycogen synthase kinase(GSK)-3, cyclin-dependent protein kinase-5, casein kinase-1, protein kinase A etc.
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Kinase Inhibitors
Lithium: Inhibits GSK-3β activity results in decreased levels of both Aβ & τ-phosphorylation τ-aggregation & NFT formation (in transgenic mice)
Other GSK-3β inhibitors are being developed, such as AR-A014418 as well as other kinase inhibitors
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Problems with Kinase InhibitorsUbiquitous expression of kinases
Pleiotropic activities in countless cellular functions
Low selectivity for specific kinases, isoforms of a particular kinase, cellular compartment and/or pathological, rather than physiological, activity of the kinase
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2. τ –aggregation Inhibitors (TAIs)
AL-108 or NAP: An intra-nasal formulation, derived from the biological activity-dependent neuroprotective protein secreted by brain in response to various insults
AL-108 interacts with microtubules, reduces τ-hyperphosphorylation & increases soluble τ levels leading to an improvement in cognition
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AL-108 recently completed phase IIa trial in patients with amnestic mild cognitive impairment demonstrated that it is safe & well tolerated
An IV formulation of NAP, known as AL-208, is also under clinical investigation
Rember™ proposed to prevent oligomerization & self-aggregation of τ & dissolve pre-formed τ-oligomers10th February 2009 53
Cont.
Pharmacotherapy of Alzheimer's disease
Strategies targeting Aβ
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Pharmacotherapy of Alzheimer's disease
Aims of therapy
Stimulating α-secretase cleavage in order to direct APP processing towards the non-amyloidogenic pathway
Suppressing β- and/or γ-secretase cleavage in order to reduce the amount of Aβ produced
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Pharmacotherapy of Alzheimer's disease
1. Inhibitors or modulators of the secretases
Numerous β- & γ–secretase inhibitors and/or modulators have been designed
But majority of these agents are not specific for the secretase cleavage of APP & thus may prevent the cleavage & processing of additional substrates, which could result in various adverse effects
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2. Aβ aggregation inhibitorsIts found that soluble Aβ monomers assume a random
coil or α-helix conformation but in AD they undergo a structural change into a pleated β–sheet
This induces the peptide to form LMW oligomers, HMW complexes, mature fibrils & amyloid plaques (APs)
As our understanding of Aβ structure improves & with advent of more advanced techniques, the development of inhibitors of Aβ oligomers will improve
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3. Amyloid-plaque degradation enhancers
Aβ can be catabolized via enzymatic degradation
Serine proteases plasmin, tissue plasminogen activator, Neprilysin (NEP) & Insulin-degrading enzyme (IDE) have been suggested as potential methods of reducing Aβ levels
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Pharmacotherapy of Alzheimer's disease
Passive or active immunizationTransgenic mouse when actively immunized
with Aβ or passively immunized with humanized anti-Aβ antibodies showed reduced Aβ and τ-pathology, neutralized soluble Aβ oligomers and improved learning
Following successful completion of the phase I trial, a phase IIa trial with AN-1792 / Betabloc was initiated
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Trial was terminated when 4 patients reported autoimmune meningoencephalitis
A subsequent autopsy analysis of a phase I study patients indicated evidence of encephalitis
A composite neuropsychological performance study has shown that the patients developing Aβ antibodies showed improvement in memory attention & concentration
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Cont.
Pharmacotherapy of Alzheimer's disease
Many patients developed anti-Aβ antibodies which was consistent with a slowing in the rate of cognitive decline 12 months after completion of the trial
Long-term clinical follow-up of 80 patients demonstrated a varied degree of Aβ plaque removal & no prevention of progressive neurodegeneration with no evidence for improved survival10th February 2009 61
Cont.
Pharmacotherapy of Alzheimer's disease
Development of IV recombinant humanized anti-Aβ monoclonal immunoglobulins (IVIg) which avoid induction of an immune response continues in parallel
Examples of passive vaccines against Aβ in various stages of research and development are:
Phase I (V950)
Completed phase II (LY2062430)
Ogoing parallel phase II & III (AAB-001/Bapineuzumab)
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Cont.
Pharmacotherapy of Alzheimer's disease
The metal hypothesis of ADIt is found that cerebral concentrations of Zn,
Cu & Fe ions are significantly elevated in AD
APs are rich in Zn, Cu & Fe
Cu2+ alters τ-structure promoting its phosphorylation & inducing its aggregation
This suggests role of metals in AD
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Pharmacotherapy of Alzheimer's disease
Age-related endogenous metal dyshomeostasis in brain allows binding of metal ions (Cu2+ & Fe3+) to Aβ
This can lead to neurotoxicity
Metallated-Aβ produces reactive oxygen species resulting in free radicals induced oxidative stress damage of lipids proteins & DNA, ultimately leading to synaptic & neuronal loss10th February 2009 64
Cont.
Pharmacotherapy of Alzheimer's disease
To restore metal homeostasis,
Inhibit Aβ-metal interactions
Inhibit metallated Aβ-catalysed oxidation
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Strategies targeting metal ions
Pharmacotherapy of Alzheimer's disease
AntioxidantsAntioxidant are capable of neutralizing free or
incorrectly bound metals thereby interfering with generation of ROS & other free radicals
Antioxidants like Estrogen, melatonin, vitamin C & E, ginkgo biloba extract, curcumin & flavonoids shown to have neuroprotective effects against Aβ-induced toxicity in cellbased experiments & animal models but have conflicting results in clinical settings
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Pharmacotherapy of Alzheimer's disease
Metal chelatorsIt binds strongly to 2 or more metal ions & form a
cyclic ring which converts metal ions into an inert form & depletes total pool of bioavailable metals
Desferrioxamine (DFO) an Fe chelator with high binding affinities for Zn, Cu & Al was the 1st such agent to enter clinical investigations for treatment of AD
DP-109 reduced formation of CAA & deposition of APs as well as it re-solubilized Aβ
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Metal complexesAn alternative approach to chelation is to
modulate metals with metallo-complexes
This serves to remove metals from biologically deleterious sites & potentially deliver them to areas of deficiency thereby maintaining overall metal homeostasis
Example: Complexes of pyrrolidine dithiocarbamate (PDTC) & Cu
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Pharmacotherapy of Alzheimer's disease
Metal-protein attenuating compounds (MPACs)
MPACs have weak, reversible affinity towards metals, which enables them to compete with endogenous ligands for metal ions & restore normal metal levels in specific cellular compartments
Example: Clioquinol
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Pharmacotherapy of Alzheimer's disease
Indian Medicinal Plants for Alzheimer’s disease / Memory improvementsBrahmi (Bacopa Monnieri)
Amla (Phyllanthus Emblica)
Guduchi (Tinospora Cordifolia)
Tulsi (Ocimum Sanctum)
Ashwagandha (Withania somnifera)
Shankhapushpi (Convolvulus pluricaulis)
Haritaki (Terminalia chebula)
Pharmacotherapy of Alzheimer's disease
Conclusion:AD pathogenesis is a complex process involving
both genetic & environmental factors
Therefore development of effective disease-modifying drugs is proving to be a difficult task
Current pharmacotherapy is not sufficient to halt the disease progression
Aβ, τ & metals are some of the therapeutic targets identified & compounds that modulate them represent promising drug candidates
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Pharmacotherapy of Alzheimer's disease 7210th February 2009
Thank you
Fe-enriched environment upregulates APP translation whereas it is down-regulated in response to an Fe-deficient environment
Increasing Cu levels in vitro can shift APP processing towards non-amyloidogenic pathway & result in decreased Aβ production
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Cont.
Pharmacotherapy of Alzheimer's disease
Metallated-Aβ also has an increased affinity for the phospholipid heads of the membrane bilayer which acts as a reductant in the production of reactive oxygen species (ROS)
Resulting radicals, such as hydrogen peroxide (H2O2) and superoxide (OH), induce oxidative stress damage of lipids, proteins and DNA, ultimately leading to synaptic and neuronal loss
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In vitro studies have shown that amyloidogenesis & fibrillogenesis can be affected by factors such as time, concentration, temperature, pH and metal ion concentration
LMW, soluble, oligomeric forms of Aβ1–42 rather than Aβ1–40 are more neurotoxic than the mature Aβ fibrils
soluble Aβ monomers assume a random coil or α-helix conformation; however, in AD they undergo a structural change into a pleated β-sheet
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Cont.