Transcript 3 rd Lecture

PHL 437/Pharmacogenomics
Third Lecture (Alzheimer's disease)
By
Abdelkader Ashour, Ph.D.
Phone: 4677212
Email: [email protected]
Neurodegenerative diseases, Introduction
 Neurodegenerative disorders are characterized by progressive and irreversible loss
of neurons from specific regions of the brain
 The most common neurodegenerative disorders include:
 Alzheimer's disease (AD), where the loss of hippocampal and cortical neurons leads to
impairment of memory and cognitive ability
 Parkinson's disease (PD), in which extensive destruction of the dopaminergic neurons of
the substantia nigra results in abnormalities in the control of movement
 The pharmacological therapy of neurodegenerative disorders is limited mostly to
symptomatic treatments that do not alter the course of the underlying disease
 Symptomatic treatment for PD, where the neurochemical deficit produced by the
disease is well defined, is, in general, relatively successful, and a number of effective
agents are available
 The available treatments for AD are much more limited in effectiveness, and new
strategies are urgently needed
Alzheimer's disease, Introduction
 AD is an irreversible, progressive brain
disease that slowly destroys memory and
thinking skills
 AD is the most frequent cause of dementia
 The prevalence of dementia increases
exponentially, from about 1% at 60–65 years
to more than 30–35% in people > 80 yr
 AD produces an impairment of cognitive
abilities that is gradual in onset but
relentless in progression
 Impairment of short-term memory usually is
the first clinical feature; retrieval of distant
memories is preserved relatively well
 As the condition progresses, additional
cognitive abilities are impaired, among them
the ability to calculate, exercise visuospatial
skills and use common objects and tools
 Death, most often from a complication of immobility such as pneumonia or pulmonary
embolism, usually ensues within 6 to 12 years of onset
Alzheimer's disease, Pathology
 Primary pathogenic events in AD are represented by genetic factors (mutations,
susceptibility SNPs) and programmed neuronal death
 Secondary pathogenic events are associated with the phenotypic expression of:
 senile plaques (b-amyloid deposition)
 neurofibrillary tangles (NFT; twisted
fibers that build up inside the nerve cell)
 synaptic loss
 dendritic desarborization
 neuronal death
 3ory and 4ory pathogenic events:
 neurotransmitter deficits
 neuroinflammatory reactions
 oxidative stress phenomena and freeradical formation
 excitotoxic reactions
 alterations in calcium homeostasis
 deficit of neurotrophic factors
 cerebrovascular perturbations
Beta-amyloid Plaques
 The presence of aggregates of b-amyloid (ABP; a short
polypeptide of 42 to 43 aa) is a constant feature of AD
 Amyloid precursor protein (APP; expressed widely by
neurons throughout the brain in normal individuals as well
as in those with AD) is the precursor to amyloid plaque
1.
1. APP is a membrane glycoprotein (contains the ABP region
(4 kDa) extending to 28 amino acids of the ectodomain
2. The production of b-amyloid from APP results from:
 Abnormal proteolytic cleavage of APP by the b-site APPcleaving enzyme BACE (b-secretase), generating a 99residue C-terminal fragment (C99) bound to the membrane
 α-Secretase cleaves APP at the ABP region to produce an
83-residue C-terminal fragment (C83)
2.
 γ-Secretase acts on the C99 and C83 substrates at the TM
domain to produce C99-derived 4-kDa ABP
 Presenilin facilitates γ-secretase cleavage of APP
3. b-amyloid fragments come together in clumps to form
plaques, disrupting the work of neurons. This affects the
hippocampus and other areas of the cerebral cortex
3.
Neurofibrillary
Tangles
 Neurons have an internal support structure partly made up of microtubules. A protein
called tau helps stabilize microtubules. In AD, tau changes, causing microtubules to
collapse, and tau proteins clump together to form neurofibrillary tangles
Alzheimer's disease, Neurochemistry
 Direct analysis of neurotransmitter content in the cerebral cortex shows a
reduction of many transmitter substances mainly acetylcholine
 The anatomical basis of the cholinergic deficit is the atrophy and
degeneration of subcortical cholinergic neurons that provide cholinergic
innervation to the whole cerebral cortex
 The deficit in AD is complex, where it involves multiple neurotransmitter
systems, including serotonin, glutamate and neuropeptides, and that in AD
there is destruction of not only cholinergic neurons but also the cortical and
hippocampal targets that receive cholinergic input
Alzheimer's disease, Pharmacogenomics
 AD is a complex disorder associated with multiple genetic defects either mutational
or of susceptibility origin
 Structural genomics studies demonstrated that more than 200 genes might be
involved in AD pathogenesis regulating dysfunctional genetic networks leading to
premature neuronal death
 Pharmacological treatment in AD accounts for 10–20% of direct costs, and fewer
than 20% of AD patients are moderate responders to conventional drugs (donepezil,
rivastigmine, galantamine, memantine), with doubtful cost-effectiveness
 The therapeutic response to drugs in AD has been shown to be genotype-specific
 Apolipoprotein E (Apo E) has been identified as the first of genetic risk factors for
AD. Four distinct isoforms of this protein (which is well known to be involved in
transport of cholesterol and lipids in blood) exist.
 Although all the isoforms carry out their primary role in lipid metabolism equally well,
individuals who are homozygous for the Apo E 4 allele ("4/4") have a much higher
lifetime risk of AD than do those homozygous for the Apo E 2 allele ("2/2")
 The mechanism by which the Apo E 4 protein increases the risk of AD is not known,
but a secondary function of the protein in b-amyloid aggregation or processing of
APP has been suggested
Alzheimer's disease, Pharmacogenomics, contd.
 The accumulation of genetic defects in AD anticipates the onset of the disease and
influence the therapeutic response of patients to conventional drugs
 Several missense mutations have been identified in APP that potentially result in
early-onset AD
 The combination of 6 ApoE genotypes with 3 PS1 genotypes and 2 PS gene related
variants generates the 36 most frequent genotypes in the AD population
 Amyloid production and deposition is increased in AD patients with PS mutations
 Patients with a defective PS2 gene exon 5 (PS2+) always show a worse therapeutic
response than PS2- patients
 The therapeutic response in AD using cholinesterase inhibitors and/or noncholinergic compounds is genotype specific
 ApoE-3/4 patients are the best responders , whereas APOE-4/4 patients are the worst
responders
 About 10–20% of Caucasians are carriers of defective cytochrome P450 2D6
polymorphic variants that alter the metabolism and effects of AD drugs