INTRODUCTION

Calcium regulates many functions in our body such as for formation of

bones, development of teeth and healthy gum. It is also necessary for blood
clotting mechanism. Calcium has natural calming and tranquilizing effect. It is
also necessary for maintaining regular heartbeat and transmission of nerve
impulse, helps lowering cholesterol, muscular growth and prevention of muscle
cramps. Calcium maintains proper cell membrane permeability and aids in
neutromuscular activity. Futhermore, calcium stops lead (Pb) from being absorbed
into bone.
Calcium ion is a ubiquitous messenger and has an important role in the
transduction of the signal leading to the cellular responses such as cell motility
changes, fertilization, neurotransmission and protein secretion as well as cell
fussion, differentiation and proliferation. (Baynes and Dominiczak, 2005) In
several research are found that dysregulation of intracellular calcium signaling has
been implicated in the phatogenesis of Alzheimers disease. (Leissring et al, 2002)
Alzheimers disease is the most common cause of dementia among older
people. Dementia is the loss of cognitive functioningthinking, remembering,
and reasoningto such an extent that it interferes with a persons daily life and
activities. (U.S. Department of Health and Human Services, 2008)
Later, progressive disorientation, memory loss, and aphasia indicate severe
cortical dysfunction, and eventually in 5 to 10 years, the patient become
profoundly disable, mute and immobile. Patients rarely become symptomatic
before 50 years of age, but the incidence of the disease rises with age, and the
prevalence roughly doubles every five years, starting from a level of 1% for the
60- to 64-year-old population and reaching 40 % or more for the 85- to 89-yearold population cohort. This progressive increase in the incidence of the disease
with age has given rise to major medical, social, and economic problems in
country with growing number of elderly individual. Most cases are sporadic,
although at least 5% to 10% of cases are familial. Pathologic changes identical to
those observe in Alzheimer diseases occur in almost all individuals with trisomy
21 who survive beyond 45 years, and a decline in cognitive can be clinically
demonstrated in many. Although pathologic examination of brain tissue remains
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necessary for the definitive diagnosis of Alzheimer disease, the combination of

clinical assessment and modern radiologic methods allows accurate diagnosis in
80% to 90% of cases. (Robbins and Cotrar, 2005:1386)
Memory problems are one of the first signs of Alzheimers disease. Some
people with memory problems have a condition called amnestic mild cognitive
impairment (MCI). People with this condition have more memory problems than
normal for people their age, but their symptoms are not as severe as those with
Alzheimers. Alzheimers disease can be definitively diagnosed only after death
by linking clinical course with an examination of brain tissue and pathology in an
autopsy. (U.S. Department of Health and Human Services, 2008)
Alzheimers disease is a complex disease, and no single magic bullet is
likely to prevent or cure it. Thats why current treatments focus on several
different aspects, including helping people maintain mental function; managing
behavioral symptoms; and slowing, delaying, or preventing the disease. (U.S.
Department of Health and Human Services, 2008)

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CONTENT
1. Definition
Alzheimers disease is an irreversible, progressive brain disease that
slowly destroys memory and thinking skills, and eventually even the ability to
carry out the simplest tasks. (U.S. Department of Health and Human Services,
2008) Clinical manifestation of Alzheimer disease is dementia that is the
progressive loss of cognitive function independent of the state of attention.
(Robbins et al, 2005: 1386)
2. Causes
This disease is related to the changes in the cerebral cortex. Regardless of
normal aging, dementia is not part of normal aging and always represents a
pathologic process. (Robbins et al, 2005: 1386) It is likely that the causes
include genetic, environmental, and lifestyle factors. Because people differ in
their genetic make-up and lifestyle, the importance of these factors for
preventing or delaying Alzheimers differs from person to person.
Cerebral cortex (Marieh, 2004: 436)
The cerebral cortex is the executive suite of the nervous system, where
our conscious mind is found. It enables us to be aware of ourselves and our
sensations, to communicate, remember, and understand, and to initiate
voluntary movements. Because it is composed of gray matter, the cerebral
cortex consist of neuron cell bodies, dendrites and unmyelinated axons (plus
associated glia and blood vessels), but no fiber tracts. It contains billions of
neurons arranged in six layers, and accounts for roughly 40% of total brain
mass. Although it is only 2-4 mm (about 1/8 inch) thick, its many
convolutions effectively triple its surface area.
The generalized region functions of the cerebral cortex are:
1. The cerebral cortex contains three kinds of functional areas: motor areas,
sensory areas, and association areas.
2. Each hemisphere is chiefly concerned with the sensory and motor and
motor functions of the opposite (contralateral) side of the body.

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3. Although largely symmetrical in structure, the two hemisphere are not

entirely equal in function. Instead, there is a lateralization (specialization)
of cortical functions.
4. The final, and perhaps most important, generalization to keep in mind is
that our approach is a gross oversimplification; no functional area of the
cortex acts alone, and conscious behavior involves the entire cortex in one
way or another.
Plaque and Neurofibril Tangles (Robbins et al, 2005: 1386)
The major microscopic abnormalities of the Alzheimer disease are
neuritric (senile) plaques, neurofibrillary tangles, and amyloid angiopathy.
All of these may be present to a lesser extent in the brains of elderly
nondemented individuals. The diagnosis of Alzheimer disease is based on
a combination of clinical and pathologic features. Several different
diagnostic methods have been proposed, which include evaluation of
different regions of the brain and various methods for estimating the
frequency of plaques and tangles. There is a fairly constant pattern of
progression of involvement of brain regions. Pathologic changes
(specifically plagues, tangles, and associated neuronal loss and glial
reaction) are evident earliest in the entorhinal cortex, then spread through
the hippocampal formation and isocortex, and then extend into the
neocortex.
Neuritic plaques are focal, spherical collections of dilated,
tortuous, silver-staining neuritic processes (dystrophic neuritis) often
around a central amyloid core, which may be surrounded by clear halo.
Neuritic plaques range in size from 20 to 200 m in diameter; microglial
cell and reactive astrocytes are present at their periphery. Plaques can be
found in the hippocampus and amygdala as well as in the neocortex,
although there is usually relative sparing of primary motor and sensory
cortices (this also applies to neurofibrillary tangles). The dystrophic
neuritis contain paired helical filaments as well as synaptic vesicle and
abnormal mitochondria. The dominant component of the plaque core is
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A, a peptide derived through specific processing events from a large

molecule, amyloid precursor protein (APP). The two dominant species A,
called A40 and A42, share an N terminus and differ in length by two
amino acids. Other proteins are present in the plaques in lesser abundance,
including

components

cytokines,

1-antichymotrypsin,

and

apoplipoproteins.
Immunostaining for A demonstrates the existence, in some
patients, of amyloid peptide deposits in lesions lacking the surrounding
neuritic reaction. These lesions, termed diffuse plaques, are found in
superficial portions of cerebral cortex as well as in basal ganglia and
cerebellar cortex. Diffuse plaques appear to represent an early stages off
plaque development, based primarily on studies of brains from individuals
with trisomy 21. In some brain regions (cerebellar cortex and striatum),
they persist as a major manifestation of the disease. While neuritic plaques
contain both A40 and A42, diffuse plaques are predominantly made up of
A42.
Neurofibrillary tangles are bundles of filaments in the cytoplasm of
the neurons that displace or encircle the nucleus. In pyramidal neurons
they often have an elongated flame shape; in rounder cells, the basket
weave of fibers around the nucleus takes on a rounded contour (globose
tangles). Neurofibllary tangles are visible as basophilic fibrillary structures
with H & E staining but are dramatically demonstrated by silver
(Bielschowsky) staining. They are commonly found in cortical neurons,
especially in the entorhinal cortex, as well as in other sites such as
pyramidal cells of the hippocampus, the amygdale, the basal forebrain, and
the raphe nuclei. Neurofibrillary tangles are insoluble and apparently
resistant to clearance in vivo, thus remaining visible in tissue sections as
ghost or tombstone tangles long after death of the parent neuron.
Mutation (Robbins et al, 2005:1389)

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Several gene loci have been identified for familial Alzheimer disease. The
first of these was the gene for APP on chromosome 21. The pathogenic
mutations in the APP gene all result in increase generation of A.
Furthermore, the development of Alzheimer disease in individuals with
trisomi, single missense and double missense of chromosome 21 has been
related to a gene dosage effect with increased production of APP and
subsequently A.
Two other genetic loci linked to early-onset familial Alzheimer disease
have been indentified on chromosomes 14 and 1; this probable account for the
majority of early-onset familial Alzheimer disease pedigrees. The genes on
these two chromosomes encode highly related intracellular proteins,
presenilin-1 (PS1) and presenilin-2 (PS2). Even before these genes were
cloned, it was recognized that the cellular phenotype of these mutation was an
increased level of A generation, particularly A42 it has now become clear
from studies of knockout mice, from directed mutatagenesis of PS1 and PS2,
from pharmacologic studies, and from biochemical purifications that the
presenilins are a component of secretase and possibly are the portion of a
multiprotein complex containing the active proteolitic site. Thus, the genetic
evidence strongly supports the notion that the underlying pathogenetic event
in AD is the accumulation of A.
Distinct from these loci in which mutations cause Alzheimer disease, one
allel (4) of the apolipoprotein E (ApoE) gene on chromosome 19 increase the
risk of Alzheimer disease and lower the age at onset of the disease.
Apoptosis and Calcium (Robbins et al, 2003: 4-6)
Increased cytosolic calcium in turn activates a variety of phospholipases
(promoting membrane damage), proteases (catabolizing structural and
membrane protein), ATAases (accelerating ATP depletion), and edonucleases
(fragmenting genetic material)
Alterations of membrane permeability due to loss ATP synthesis or
resulting from calcium-mediated phospholipase activation. A loss of
membrane barriers lead to a breakdown of the concentration gradients of
metabolites necessary to maintain normal metabolic activities.
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Increases in cytosolic calcium, intracellular oxidative stress, and lipid

breakdown products all culminate in the formation of high-conductance
channels of the inner mitochondrial membrane. These nonselective pores
allow the proton gradient across the mitochondrial membrane to dissipate,
thereby preventing ATP generation.
Apoptosis occurs as s result of an internally controlled suicide program,
after which the dead cells are removed with minimal disruption of the
surrounding tissue. This occurs in physiologic states when unwanted cells are
to be eliminated, as well as in a variety of pathologic states.
The mechanism underlying apoptosis are the subject of extensive and
evolving investigation. The basic process can be understood as four separable
but overlapping components.
1. Signaling. Apoptosis may be triggered by a variety of signals ranging from
an intrinsic programmed event, a lack of growth factor, specific receptorligand interactions, release of granzymes from cytotoxic T cells, or
selected injurious agents. Transmembrane signals may either suppress
preexisting death programs (and are thus survival stimuli) or initiate a
death cascade. The most important in this latter group are those that belong
to the tumor necrosis factor receptor (TNFR) superfamily of plasma
membrane molecules (this include the FAS surface molecule). These
plasma membrane receptor share an intracellular death domain protein
sequence that when oligomerized (typically trimerized) leads to activation
of initiator caspases and a cascade of enzyme activation culminating in cell
death.
2. Control and integration. This is accomplished by specific proteins that
connect the original death signals to the final execution program. These
protein are important because their actions may result in either
commitment or abortion of potentially lethal signals. There are two
broad pathways in this stage: (1) direct transmission of death signals by
specific adapter proteins to the execution mechanism; and (2) regulation of
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mitochondrial permeability by members of the BCL-2 family of proteins.

Recall that various agonists (Ca++, free radicals, etc.) can affect
mitochondria

by

causing

mitochondrial

permeability

transitions.

Formation of pores within the inner mitochondrial membrane results in

reduction of the membrane potential, with diminished ATP production and
mitochondrial swelling; increased permeability of outer mitochondrial
membranes releases the apoptotic trigger, cytochrom c, into the cytosol. It
is speculated that release cytochrome c bind certain cytosolic proteins (e.g.
proapototic protease-activating factor, or Apaf-1) and activates them,
triggering execution caspase activation and setting in motion the
proteolytic events that kill the cell. BCL-2 (found in the mitochondrial
membrane) suppresses apoptosis by preventing increased mitochondrial
permeability and by stabilizing proteins like Apaf-1 so that caspase
activation does not occur. Other members of the BCL-2 family bind to
BCL-2 and modulate its antiapoptotic effect; thus, BCL-XL inhibit
apoptosis while BAX and BAD promote programmed cell death.
3. Excecution. This final pathway of apoptosis is characterized by a
distinctive constellation of biochemical events that result from the
synthesis and/or activation of a number of cytostolic catabolic enzymes. It
culminates in the morphologic changes describe earlier. Although there are
subtle variations, the final execution pathways exhibit common themes
generally applicable to all form of apoptosis.
4. Removal of dead cells. Apoptotic cell in their fragments have marker
molecules on their surface that facilitate uptake and disposal by adjacent
cells or phagocytes. This occurs by the flipping of phosphatidylserine from
the inner cytoplasmic face of the apoptotic cells to the extracellular face.
This and other alterations allow the early recognition and phagocytosis of
apoptotic cells without release of proinflammatory mediators. The process
is so efficient that dead cells disappear without leaving a trace, and
inflammation is virtually absent.
3. Pathophysiology
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Mutation of chromosome 21, 14 and 1 can increase Amiloid Beta (A)

production. Chromosome 19 also mutated and it can increase risk of
development and decrease age at onset of Alzheimer disease. Gene of
chromosome 21 which have been mutated is amiloid precursor protein (APP).
This mutation can be single missense mutation, double missense mutation or
trysomy 21.Two other genetic loci linked to Alzheimer disease are
chromosomes 14 in presenilin 1 (PS1) and chromoseome 1in Presinilin 2
(PS2).
The pathogenic mutation in the APP gene all result in increase generation
of A. Amyloid can activate G protein couple receptor and also it form
calcium permeable pores. G protein couple receptor is an integral membrane
protein that regulate the transduction of transmembrane signal from cell
surface receptor to a variety of the intracellular effector. Amyloid beta can
influence the calcium influx from endoplasmic reticulum to cytoplasm.
Calcium permeable pore also have the same role in increasing the number
of calcium in the cytoplasm. The calcium ion can enter this pore membrane
and it also accumulated with the calcium from the endoplasmic reticulum.
Increased number of calcium in cytoplasm then activate many kind of
enzyme include ATPase, phospolipase, protease and endonuclease. This
condition can cause decreasing of ATP and phospolipid, disruption of
membrane and cytosceletal protein, and also can make nuclear chromosome
damage. The consequences of increase cytosolic calcium finally make the cell
in the cerebral cortex undergo apoptosis. Apoptosis in this part of the brain
correlate with lost of cognitive functioning like thinking, remembering and
reasoning.

The pathophysiology of Alzheimers disease related to dyshomeostasis of

calcium can be shown in figure.1 below.

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Mutation
Mutation of
of
chromosome
chromosome
21,
21, 14,
14, 1,
1, 19
19

Altered
Altered
APP
APP
processin
processin
g
g

Increase
Increase
A
A
productio
productio
n
n

Calcium
Calcium
permeable
permeable
pore
pore

Plaque
Plaque

Activate
Activate GGprotein-coupled
protein-coupled
receptor
receptor

Destabilization
Destabilization of
of
calcium
calcium
homeostasis
homeostasis

Calcium-store
Calcium-store
level
level
increased
increased

Activation
Activation of
of
enzymes
enzymes

ATPase
ATPase

Decrease
Decrease ATP
ATP

ALZHEIMER

Phosphholipase
Phosphholipase

Decrease
Decrease
phospholipid
phospholipid

Protease
Protease

Disruption
Disruption of
of
membrane
membrane
and
and
cytoskeletal
cytoskeletal
proteins
proteins

Endonuclease
Endonuclease

Nuclear
Nuclear
chromatid
chromatid
damage
damage

APOPTOS
IS

4. Diagnose Alzheimer
Alzheimers disease can be definitively diagnosed only after death by
linking clinical course with an examination of brain tissue and pathology in an
autopsy. But doctors now have several methods and tools to help them
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determine fairly accurately whether a person who is having memory problems

has possible Alzheimers disease (dementia may be due to another cause) or
probable Alzheimers disease (no other cause for dementia can be found).
To diagnose Alzheimers, doctors: (U.S. Department of Health and Human
Services, 2008)
1. Ask questions about the persons overall health, past medical
problems, ability to carry out daily activities, and changes in behavior
and personality.
2. Conduct tests of memory, problem solving, attention, counting, and
language.
3. Carry out medical tests
4. Perform brain scans, such as computerized tomography (CT) or
magnetic resonance imaging (MRI)

CONCLUSION
Calcium is essential for maintain system in our body. Dysregulation of
intracellular calcium has been implicated in the pathogenesis of Alzheimer
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disease. Mutation of some gene such as in the chromosome 21, 1, 14, 19 is

correlate in increasing the production of A and it will form some plaque on
cerebral cortex. This correlation have significant effect in increasing the number
of calcium in cytoplasm. Abnormal accumulation of calcium in the intracellular
cause the activation of some enzyme such as protease, ATPase, endonuclease, and
phospholipase. These enzymes has significant control in apoptosis. The neuron
cell undergo apoptosis in the cerebral cortex will lead to the Alzheimers disease.

REFFERENCE
LaFerla, Frank M. 2002. Calcium Dyshomeostasis and Intracellular Signaling
in Alzheimers Disease Vol. 3. www.nature.com/reviews/neuro accessed: 26
November 2010
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Marieh, Elain N. 2004. Human Anatomy & Physiology 6th edition. San
Fransisco: Pizarsow. Pp. 436
Robbins et al. 2005. Pathologic Basis of Disease 7th edition. Philadelphia:
Elsevier Inc. Pp. 1386 - 1389
Robbins et al.2003. Basic Pathology 7th edition. Philadelphia: Elsevier Inc.
Rubin, Emanuel. 2001. Essential Pathology 3rd edition. Pennsylvania:
Lippincott Williams & Wilkins. Pp. 742 -744
Sperelakis, Nicholas. 2001.cell physiology sourcebook 3rd edition.California:
Academic Press. Pp 1172
U.S. Department of Health and Human Services. 2010. Alzheimers DiseaseNIH

publication.

www.nihseniorhealth.gov/alzheimerdisease/toc.html

accessed: 26 November 2010

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