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


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

10th February 2009 3


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


Symptoms of ADGradually worsening difficulty in

remembering new information Confusion, disorganized thinking,

impaired judgment, trouble expressing themselves

Disorientation to time, space & location



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



EtiologyAdvancing Age

Female sex

Family history

Trauma

Education

Environmental factors: Aluminum, Mercury, Viruses

Vascular diseases: Stroke10th February 2009 7


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


Cont.


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


Cont.


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


Cont.


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



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


10th February 2009 Pharmacotherapy of Alzheimer's disease 13


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


Contd.

Pharmacotherapy of Alzheimer's disease10th February 2009 15


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


Contd.


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


Contd.

10th February 2009Pharmacotherapy of Alzheimer's disease 18


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



Gross Appearance



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)


Hallmark of AD:


Microscopic features



Current Pharmacotherapy



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



Current treatment

Acetylcholinesterase inhibitors (AChEIs):

Tacrine, Donepezil, Galantamine, Rivastigmine &

Huperzine A

Non-competitive N-methyl-D-aspartate (NMDA)

receptor antagonist:

Memantine, Dimebolin



Acetylcholinesterase inhibitors


AChEI


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



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


Cont.


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



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


Donepezil


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


Contd.


NMDA receptor antagonist

Acts by blocking overexcited NMDA receptors which blocks entry of Ca++ thereby decreasing glutamate release & inhibiting processes which led to neurotoxicity



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



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


Cont.


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




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)



It has the following recommendations:

Assessment Monitor Changes

Reassess Frequently

Identify Support

Identify Culture & Values

Assess Capacity



Treatment Develop Treatment Plan

Treat Behavioural Symptoms

Non-Pharmacological Treatment First

Treat Co-Morbid Conditions

Provide End-of-Life Care



Patient & family education & supportIntegrate Medical Care & Support

Discuss Diagnosis & Treatment

Involve Early-Stage Patients

Discuss Stages

Discuss End-of-Life Decisions



Legal considerationsPlanning

Capacity Evaluations

Elder Abuse

Driving





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



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



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



Novel targets


Strategies targeting τ-protein



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.



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



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



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



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.


Strategies targeting Aβ



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



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



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



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



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



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


Cont.


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.


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)


Cont.


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



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.


To restore metal homeostasis,

Inhibit Aβ-metal interactions

Inhibit metallated Aβ-catalysed oxidation


Strategies targeting metal ions


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



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



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



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



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)


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

73

Cont.


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


Cont.

Health & Medicine

Pharmacotherapy of Alzheimer's Disease