Transcript Alzheimer_Disease

Alzheimer Disease
Dr. Hazar
322-PHL
2011- 1432
The year 2006 is the centenary of the famous
presentation of Alois Alzheimer which first described the
neuropathology of Alzheimer’s disease (AD).


Alois Alzheimer (b. 1864–d. 1915)
Alzheimer described the
results of his postmortem
studies on a 51-year-oldfemale patient known as
Auguste D., who had suffered
from a progressive presenile
dementia
Described a relatively young
patient who had developed a
rapid loss of memory and had
become disoriented in time and
space.
Alois Alzheimer




As the illness progressed, she became bedridden
and incontinent. She died four and a half years
after the onset of illness.
Post-mortem examination revealed an evenly
atrophic brain with striking neurofibrillary
pathology.
Alzheimer also described the presence of unusual
deposits in the cortex that were refractory to
staining.
His famous paper (Alzheimer 1907)
Alzheimer’s Disease



Alzheimer’s disease is the most common
form of dementia. accounting for 50–60%
of all cases.
Dementia is a syndrome that exhibits
impaired short-term and long term memory
as its most prominent feature.
Forgetfulness is the primary complaints of
patients.
Cholinergic hypothesis


The cholinergic hypothesis in Alzheimer’s disease
states that degeneration of cholinergic neurons
in the basal forebrain nuclei causes disturbances
in presynaptic cholinergic terminals in the
hippocampus and neocortex, which is important
for memory disturbances and other cognitive
symptoms.
Potentation of the activity of the central
cholinergic pathway is one strategy for the
symptomatic treatment of cognitive dysfunction
in AD.
Acetylcholinesterase inhibitors
Tacrine



Tacrine, the first agent approved for symptomatic
treatment of mild to moderate AD
Inhibit both acetylcholineesterase and
butyrylcholineesterase (BuCHE)
Low bioavailability, short half-life (multiple doses)
Tacrine
Side effect:


Nausea, vomiting , diarrhea,
abdominal pain.
Elevation of alanine
aminotransferase (ALT) levels
Donepezil




Second generation cholinesterase inhibitors
Selective Acetylcholinestearse than
(BuCHE)
Completely bioavailability, once daily
Side effect: cholinergic activity (nausea,
diarrhea, headache)
Rivastigmine

Inhibit activity of both AChE and BuChE by
binding to esteratic site of both enzymes
and slowly dissociates.

Called Pseudo-irreversible

Twice daily
Galantamine




Inhibit AChE.
allosteric modulation of nicotinic
acetylcholine receptors
It stimulates nicotinic receptors at a site
distinct from that stimulated by
acetylcholine action that does not rely on
the presence of Ach
Metabolized by CYP2D6
Glutamate theory



Glutamate is the major excitatory
neurotransmitter in the central nervous
system.
An over activation of glutamate receptors,
and particularly of N-methyl-D-aspartate
(NMDA) receptors, leads to an immediate
rise in calcium ions (cell death)
Memantine blocks glutamate-mediated
excitotoxicity
Glutamate theory



Memantine was approved for the treatment of
moderate and severe AD case as early as in
February 2002.
The basis for this approval was the result of two
randomized placebo-controlled clinical studies that
have showed a positive effect in a later stage of
this disease (Reisberg et al. 2003).
It only affects pathophysiological conditions
(NMDA receptor over activation) and leaves
physiological neurotransmission unchanged.
The amyloid cascade hypothesis



Amyloid precursor protein (APP) is a protein
containing 770 amino acids
Cleaved into peptides by three enzymes:
alpha, beta and gamma secretase.
APP is mainly formed by a two step
process:
If alpha secretase initially cleaves APP, alpha-soluble APP (αsAPP) is formed and eventually becomes a benign peptide.
When beta secretase initially cleaves APP, it becomes beta soluble APP
(β-sAPP). β -sAPP can subsequently be cleaved by gamma secretase at
two different sites producing harmful peptides such as Ab 40 and Ab
42.
The amyloid cascade hypothesis


There are two types of beta secretase betasite APP cleaving enzyme 1,2 (BACE 1,
BACE 2)
Two forms of gamma secretase (presenilin
1, presenilin 2).
Alzheimer and genetics





Less than 10% of the AD cases are
autosomal dominantly inherited and are
linked to one of three different
chromosomes.
To date, mutations in the following genes
have been described to be causative for AD
presenilin-1 gene on chromosome 14,
presenilin-2 gene on chromosome 1
amyloid precursor protein gene on
chromosome 21.
Alzheimer and genetics

People that carry mutations in any
one
of
these
genes
usually
experience a very early onset of AD,
well below 60 years of age
Potential target in the future

β-secretase inhibitors

γ-Secretase inhibitors
Metal Ions and Amyloid β proteins


Aβ itself can act as a metalloprotein
displaying high affinity for copper
(Cu2+) and zinc (Zn2+).
Interaction between amyloid and
metal ions might mediate amyloid
aggregation and amyloid nerve cell
toxicity
Ion chelators

clioquinol is a hydrophobic compound
that acts as a copper and zinc chelator

It can readily cross the blood brain barrier


Clioquinol was used decades ago as an
oral antiamoebic compound, but it has
been withdrawn from the market because
of possible neuropathic side-effects.
Phase II clinical trial
Disease-related changes of the tau


tau is a protein involves binding and
stabilization of microtubule
structure and function.
The microtubule network in the cell
is required for the transport of
proteins.
Tau, calpains and apoptosis

cyclin-dependent kinase 5 (cdk5), which promote
phosphorylation of tau

p35 is a neuron-specific activator of cdk5

conversion of p35 into p25 by calpain-dependent proteolysis
causes prolonged activation and mislocalization of cdk5.

Consequently, the p25 ⁄ cdk5 kinase hyperphosphorylates
tau, disrupts the cytoskeleton, and promotes apoptosis of
primary neurons.
Tau, calpains and apoptosis

preaggregated Aβ induced the
generation of a neurotoxic 17-kDa
tau fragment

prevented by a calpain inhibitor

Prevented by anti-tau.
Apolipoprotein E4 (ApoE4)


Approximately 15% of the human
population inherit an allele,
apolipoprotein E4 (ApoE4) which
can increase the risk for AD by
approximately 3-fold .
The APO E gene comes in three
flavors, the epsilon 2, epsilon 3 and
epsilon 4 alleles.
Apolipoprotein E4 (ApoE4)


In healthy people, the frequency of the
epsilon 4 allele is 10%; in AD patients,
this frequency is increased to over 40%.
The existence of one or two copies of the
epsilon 4 allele increases of the AD onset
in a dose-dependant manner
Apolipoprotein E4 (ApoE4)


This allele increases cholesterol
concentrations and may be responsible
for augmenting the amount of Aβ or
decreasing its clearance (4, 5).
the formation of myelin is dependent on
cholesterol, it has been suggested that
cholesterol may be partially responsible
for the progression of AD
Statins for Alzheimer


Medications which inhibit 3-hydroxy-3methylglutaryl- coenzyme A (HMG-CoA)
reductase have been proven to reduce
serum cholesterol, and low density
lipoproteins (LDL)
lovastatin, simvastatin and cerivastatin
cross BBB reduce the amount of Aβ
peptides by reducing cholesterol from the
blood and/or the cerebrospinal fluid (CSF)
Anti-inflammatory



Inflammation is also occurring during the
development of AD (Rogers et al. 1992; Akiyama et
al. 2000).
senile plaques attracting activated microglia,
reactive astrocytes, cytokines and complement
components (Akiyama et al. 2000)
Reduction in the risk of AD associated with a chronic
use of non-steroidal anti-inflammatory drugs
(NSAID) ibuprofen, indomethacin and sulindac – but
no other NSAID decrease the release of Aβ
Treatment of behavioural signs


Behavioural signs, such as
aggression, psychomotor agitation,
and psychosis (hallucinations and
delusions)
Atypical antipsychotic drugs
Dementia and Alzheimer's disease





Alzheimer's disease (AD) is a common age-related
dementia, distinct from vascular dementia associated
with brain infarction.
The main pathological features of AD comprise amyloid
plaques, neurofibrillary tangles and a loss of neurons
(particularly cholinergic neurons of the basal forebrain).
Amyloid plaques consist of the Aβ fragment of amyloid
precursor protein (APP), a normal neuronal membrane
protein, produced by the action of β- and γ-secretases.
AD is associated with excessive Aβ formation, resulting
in neurotoxicity.
Familial AD (rare) results from mutations in the genes
for APP, or the unrelated presenilin, both of which cause
increased Aβ formation.
Neurofibrillary tangles comprise aggregates of a highly
phosphorylated form of a normal neuronal protein
(Tau). The relationship of these structures to
neurodegeneration is not known.




Loss of cholinergic neurons is believed to
account for much of the learning and
memory deficit in AD.
Anticholinesterases (tacrine, donepezil,
rivastigmine) give proven, though limited,
benefit in AD.
Many other drugs, including putative
vasodilators (dihydroergotamine),
muscarinic agonists (arecoline, pilocarpine )
and cognition enhancers (piracetam,
aniracetam), give no demonstrable benefit
and are not officially approved.
Certain anti-inflammatory drugs, and also
clioquinol (a metal chelating agent), may
retard neurodegeneration and are
undergoing clinical evaluation.