Transcript ALZHEIMER DISEASE - University of Guelph

ALZHEIMER’S DISEASE
Erin Dancey
Overview
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Alzheimer’s is the most common cause of
dementia in adult life and is associated with the
selective damage of brain regions and neural
circuits critical for memory and cognition
The pathogenesis of this disease is complex, and
involves many molecular, cellular, and
physiological pathologies
The neurons in the neocortex, hippocampus,
amygdala, and the basal forebrain cholinergic
system are the most affected brain regions
Amyloid Plaque Formation
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Alzheimer’s patients show numerous plaques which are
composed of 4 kD Amyloid-beta (A-beta) peptides, which
are derived from beta amyloid precursor proteins (APPs)
APP is a membrane associated glycoprotein of 110-135
kDa that is proposed to normally behave in the brain as
a cell surface signaling molecule
A-beta peptides are generated in the endosomal
compartment and in the endoplasmic reticulum or golgi
complex by endoproteolytic cleavage of APP by Beta,
alpha, and gamma secretases
Presenilins
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Presenilin 1 (PS1) and presenilin 2 (PS2) are
highly homologous 43-50 kD proteins with eight
transmembrane domains
Presenilin’s make crucial contributions to
neurodegeneration in AD
Presenilin’s are crucial components of the
enzymes that work to cleave APP, and mutations
in presenilins cause the production of A-beta42
and A-beta43 peptides (insoluble forms of Abeta)
The production of A-beta
production by processing of APP
Amyloid Plaque formation
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About 90% of the secreted A-beta peptides
formed from processing of APP are A-beta40, a
soluble form of the peptide
About 10% of secreted A-beta peptides are Abeta42 and A-beta43
A-beta42 and A-beta43 are highly fibrillogenic,
readily aggregated, and neurotoxic
Amyloid Plaque formation
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Alignment of several strands of A-beta
show that A-beta42 and A-beta43
preferentially form networks of salt
linkages and strong hydrogen bonds
between ionized side chains of opposite
charge which thus form the observed
plaques
Alignment of the sequence of the
42 residue peptide of the plaque of
Alzheimer’s disease
Schematic representation of a
parallel beta sheet in an amyloid
fibril
Micrographs of amyloid fibrils
Micrograph of amyloid fibres
Neurofibrillary pathology
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Intracellularly, alzheimer’s patients show
neurofibrillary pathology
Affected neurons accumulate tau and
ubiquitin immunoreactivities within
neurofibrillary tangles, in cell bodies and
dendrites, and in dystrophic neuritis
Plasmin
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In the brain, plasminogen and its proteolytic
fragment are abundant in the hippocampus
It has been hypothesized that brains of patients
with AD may have lower levels of plasmin
The higher production of amyloid peptide
together with less efficient degradation would to
A-beta accumulation and aggregation
Early Onset Alzheimer’s
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Most cases of early onset AD are familial
autosomal dominant disorders caused by
mutations in APP, PS1, and PS2
Various substitutions have been studied
and they have found various mutations
that cause the individuals to secrete a
higher fraction of A-beta42 and/or Abeta43 peptides
Late Onset Alzheimer’s
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In late onset alzheimer’s, there are no
specific gene mutations that are
associated with the inheritance of the
disease
However, specific alleles of apoliprotein E4
(apoE) and alpha2 macroglobulin are
associated with increased risk of
alzheimers
Amyloid Hypothesis
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The trigger for alzheimer’s disease is the A-beta
peptide, and the accumulation of this peptide in
the form of plaques is the initiating molecular
event
The plaques trigger an inflammatory response,
neuronal cell death, and gradual cognitive
decline
The rest of the disease process, including
formation of neurofibrillary tangles containing
tau protein, is caused by an imbalance between
A-beta production and A-beta clearance
The sequence of pathogenic events
leading to AD proposed by the
amyloid hypothesis
Postulated evolution of structural
abnormalities and evidence of Abeta deposits in the hippocampus
Support for the Amyloid Hypothesis
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The A-beta peptide is the primary component of
the necrotic brain tissue
Mutations in the gene encoding the tau proteins
cause frontotemporal dementia with
parkinsonism
However, parkinsonism is characterized by
severe deposition of tau in neurofibril tangles in
the brain, but there is no deposition of amyloid
Support for the Amyloid Hypothesis
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Growing evidence indicates that genetic
variability in A-beta catabolism and
clearance may contribute to the risk of
late onset of AD
Problems with the amyloid
hypothesis
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The number of amyloid deposits in the brain do not
correlate well with the degree of cognitive impairment
that the patient experienced in life. In some cases,
individuals without symptoms of AD have many cortical
A-beta deposits. However, in these cases, these are
diffuse amyloid plaques that are not associated with
surrounding necrotic and glial pathology
The amyloid hypothesis remains controversial because a
specific neurotoxic species of A-beta and its effects on
neuronal function have not been defined in vivo
Problems with the amyloid
hypothesis
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Another concern is that the fact that all AD causing
mutations in APP, PS1, or PS2 increase A-beta
deposition, yet the degree to which a particular mutation
affects A-beta production in cell culture shows no simple
correlation with the age at which if first produces
symptoms
The degree of dementia appears to correlate with
soluble A-beta species. Several lines of evidence have
converged recently to demonstrate that soluble
oligomers of A-beta, instead of monomers or insoluble
amyloid fibrils, may be responsible for synaptic
dysfunction in the brains of AD patients and in animal
models
Calcium Hypothesis
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Calcium modulates many neural processes, including
synaptic plasticity and apoptosis
Dysregulation of intracellular calcium signaling has been
implicated in the pathogenesis of alzheimer’s disease
Increased intracellular calcium elicits the characteristic
lesions of this disorder, including the accumulation of
amyloid-beta, the hyperphosphorylation of TAU and
neuronal death
Every gene that is known to increase susceptibility to
Alzheimer’s disease also modulates some aspect of
calcium signaling
Calcium Hypothesis
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The disruption of calcium homeostasis
might be one of the principal mechanisms
by which A-beta manifests its neurotoxicity
A-beta has been shown to destabilize
neuronal calcium homeostasis, generally
leading to an increase in cytosolic calcium
which can then trigger neuronal apoptosis
Treatment Strategies
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1. One could attempt to partially inhibit proteases that
generate A-beta from APP
2. One could attempt to prevent the oligomerization of
A-beta or enhance clearance from the cerebral cortex
3. An anti-inflammatory strategy based on the
observation that a cellular inflammatory response in the
cerebral cortex is elicited by the progressive
accumulation of A-beta
Treatment Strategies
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4. Based on modulating cholesterol
homeostasis. Chronic use of cholesterol
lowering drugs have been associated with a
lower incidence of Alzheimer’s disease
5. Based on the observation that A-beta
aggregation is, in part, dependent on the metal
ions zinc and copper. This strategy reasons that
chelation of these ions in vivo may prevent Abeta deposition
References
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1. Price, D.L., Sisodia, S.S., and Borchelt, D.R. (1998). Genetic
Neurodegenerative Diseases: The Human Illness and Transgenic
Models. Science 282, 1079-1093
2. Vassar, R., and Bennet, B.D. (1998) Beta-secretase cleavage of
alzheimer’s amyloid precursor protein by the transmembrane
aspartic protease BACE. Science 286, 5440-5464
3. LaFerla, F.M. (2002) Calcium dyshomeostasis and intracellular
signalling in alzheimer’s disease. Nature Reviews Neuroscience 3,
862-872
4. Gregersen, N., Bross, P., and Andresen, B.S. (2001) The role of
chaperone-assisted folding and quality control in inborn errors of
metabolism: Protein folding disorders. Journal of Inherited
Metabolic Disorders 24, 189-212