Link between Melatonin and Alzheimer’s Disease
Introduction
Alzheimer’s
is the most common and one of the most profound degenerative conditions of the
brain that is affecting the age old society from ages. Although the disease can
be seen in every age group but it is mostly prevalent in elderly age group. The
incidence of clinically diagnosed Alzheimer’s disease is similar throughout the
world, and it increases with age, approximately 3 new cases yearly 100,000
persons younger than age 60 years and a staggering 125 new cases per 100000 of
those older than 60 years. Several etiological factors such as birth order,
mother’s age at birth and a family history of Down’s syndrome may have a
possibility of developing Alzheimer’s disease in the later part of the life. The
familial occurrence of Alzheimer’s disease has been well established. In less
than one percent of such cases there is a dominant inheritance pattern with a
high degree of penetration and appearance of disease at younger age group. Reports
of substantial familial aggregation of dementia without a specific pattern of
inheritance also suggest the operation of more than one genetic factor. Many studies
have documented an increase in the risk of ostensibly sporadic Alzheimer’s
disease among the first degree relatives of patient with this disorder. Reports
suggest that women are in the greater side of developing this disease. Genetic studies
are difficult to carry out because the disease does not appear at the same age
in a given proband. Even in identical twin, the disease may develop at the age
of 60 years in one of the pair and at 80 years in the other. Death from other
causes may prevent its detection.
Understanding Alzheimer’s in a broader sense
The disease onset is slightly difficult to
understand by the patient in the early stages and the patient might come to
attention months or years after the de-orientation begins in the brain. Manifestation
of the process begins by an unusual degree of confusion in relation to a
febrile illness, an operation, mild head injury or the institution of new
medicines. The gradual development of forgetfulness is the main substantial clinical
feature of the disease. The words that were seldom used become elusive. Little
used words from an earlier period of life also tend to be lost. Once the memory
disorder has become pronounced in the prototypic disorder, other failures in
the cerebral function become increasingly apparent. There is development of the
halting speech because of the failure in generating needed words. The same
difficulty also occurs while writing words. Almost imperceptible at first these
disturbances of language become increasingly apparent as the disease
progresses. The range of vocabulary and the accuracy of spelling are reduced. Finally
after many years of illness there is a failure to speak in full sentence.
1. 1. Amnesia: - Disproportionate failure of episodic memory
but immediate memory remains intact. There is problem in the short term and
long term memory failures.
2. 2. Dysnomia: -The forgetting of words, especially proper
names, may first bring the patient to a neurologist. Later the difficulty
involves common nouns and progresses to the point where fluency of speech is
seriously impaired. The patient finds it difficult to complete the sentence and
as result the sentence is left unfinished.
3. 3. Visuospatial disorientation: - Parietooccipital functions
are sometimes deranged in the course of the disease and in a few cases may fail
while other functions are relatively preserved. When it occurs in a pure form
it is termed as posterior cortical atrophy. Prosopagnosia, losing one’s way in
a familiar surroundings or inability to interpret road map, to distinguish from
right to left, or to park the car in a garage are some of the symptomatic features
that the patient used to face when the disease progresses.
4. 4. Paranoia and personality changes: - The bizarre behavior
of the patient occasionally assumes prominence. The patient becomes convinced
that the relatives are stealing his possessions or that an elderly and even infirm
spouse is guilty of infidelity.
5. 5. Executive dysfunction: - The patients display early
difficulties in co-coordinating and planning tasks and following complex
conversations and instructions. They may become disinclined to participate in
social activities and become withdrawn or quieter than usual. Some are able to
express that they feel confused but more often it is the family that brings
these changes to attention.
Pathology
The brain presents diffusely atrophied
appearance sand its weight is usually reduced by 20% or more. Cerebral
convolutions are narrowed and sulci are widened. There is enlargement of the
lateral and third ventricle. Loss of nerve cells is the most prominent features
of the disease. Marked neuronal loss in the hippocampus, adjacent parts of the
medial temporal cortex- the parahippocampal gyri and subculum are affected. The
anterior nuclei of the thalamus, septal nuclei, diagonal band of Broca,
amygdale and particular parts of the brainstem of the monoaminergic system are
also depleted. Neurons of the nucleus basalis of the Meynert and locus ceruleus
are also reduced in number, a finding that has aroused interest because of its
putative role of the former in memory function. In the cerebral cortex, the
cell predominantly affects the large pyramidal neurons. Residual neurons are
observed to have volume and ribonucleoprotein; their dendrites are diminished
and crowd one another owing to the loss of synapses and neuropil. Astrocytic
hypertrophy is in evidence as a compensatory or reparative process, most
prominent in layers III and V.
Three
microscopic changes give the disease a distinctive character:-
1. 1. The presence within the nerve cell cytoplasm of thick,
fiber like strand of silver staining material, also in the form of loops, coils
or tangled masses. These strands are composed of a hyperphosphorylated form of
the micro tubular proteins, tau, and appear as pairs of helical filaments.
2. 2. Spherical deposits of amorphous material scattered throughout
the cerebral cortex and easily seen with periodic acid –Schiff; the core of the
aggregates is the protein amyloid, surrounded by degenerating nerve terminals
that stains with silver. Amyloid is also scattered throughout the cerebral
cortex in a nascent “diffuse” form, without organization or core formation and
then is appreciated mainly by immune histo chemical methods, as well as
deposition in the walls of small blood vessels near the plaques, so called
cognophilic angiopathy.
3. 3. Granulovascular degeneration of the neurons, most evident
in the pyramidal layer of the hippocampus.
Pathogenesis of Alzheimer’s Disease
The Aβ protein is a small portion of a large entity,
the amyloid precursor protein (APP), which is normally bound to neuronal
membranes. The Aβ protein is cleaved from the APP by the action of proteases termed
α, β and γ secretase. During normal cellular metabolism, APP is cleaved by
either α or β secretase. The product of this reaction is then cleaved by the γ
secretase isoform of the enzyme. The sequential cleavage by α and then γ
produces tiny fragments that are not toxic to neurons. However, cleavage by β
and then γ results in a 40 amino acids product, Aβ40, and a longer 42amino
acids form. The latter Aβ42 form is toxic in several models of Alzheimer’s disease,
and it has been proposed that the ratio of Aβ42 to Aβ40 is critical to the
neuronal toxicity of amyloid.
Several pieces of evidence favors the view that elevation of the levels of Aβ42 leads to aggregation of amyloid and then to neuronal toxicity. It appears that the diffuse deposition of Aβ42 precedes the formation of better defined neurofibrils and plaques. The fact that the gene coding for APP is located on chromosome 21, one of the regions linked to one type of familial Alzheimer’s disease and the duplicated chromosome in Down’s syndrome, in which Alzheimer’s changes almost inevitably occur with aging, suggest that the over production of amyloid and all its Aβ residues are causative factors in the disease. Furthermore, the ratio of Aβ42 to Aβ40 is increased in Down syndrome. Another suggestive connection has been the finding that there are genetic defects in the genes encoding APP and in a pair of endosomal proteins termed presenilin 1 and 2 in some familial forms of Alzheimer’s disease. The presenilins interact with, or may be a component of, γ secretase, the enzymes that produces the Aβ42 fragment. Mutations of presenilin 1 and 2 also increase the relative levels of Aβ42. It should be noted that mutations of the APP and presenilin genes explain a very small proportion of Alzheimer’s cases.
It must be emphasized, however, that there is still uncertainity regarding the relationship of amyloid deposition to the loss of neurons and brain atrophy. Alternatively, soluble oligomeres of Aβ amyloid may be the toxic agents, whereas the emphasis until now has been on the effects of visible assemblies of insoluble amyloid fibrils. Similarly, TDP-43, the product of inadequate functioning of the progranulin gene, is also deposited in the neurons and may play a substantial role in the severity of expression of Alzheimer’s disease; the protein has been implicated in the pathogenesis of fronto-temporal dementia and motor neuron disease.
Neurotransmitter abnormalities
Considerable interest was created in the late 1970’s by the finding of a marked reduction in choline acetyltransferase and acetylcholine in the hippocampus and neocortex of patients with Alzheimer’s disease. This loss of cholinergic synthetic capacity was attributed to a reduction in the number of cells in the basal forebrain nuclei, from which the major portion of neocortical cholinergic terminals originate. However, a 50 percent reduction in ChAT activity has been found in regions such as the caudate nucleus, which shows neither plaques nor tangles. The specificity of the nucleus basalis cholinergic changes has been questioned for other reasons as well. For one, Alzheimer’s brain also shows a loss of monoaminergic neurons and a diminution of noradrenergic, gabanergic, and serotonergic functions in the affected neocortex. The concentration of aminoacids transmitters, particularly of glutamate, is also reduced in cortical and subcortical areas and the concentration of several neuropeptide transmitters-notably substance P, somatostanin and cholecystokinin are likewise low- but it has not been determined whether any of these biochemical abnormalities, including the cholinergic ones, are primary or secondary to heterogenous neuronal loss. Nevertheless, the administration of cholinomimetics- acetylcholine precursors, degradation inhibitors, or muscarinic agonists that act directly on postsynaptic receptors-have had a mild and unsustained therapeutic effect1.
Melatonin in Alzheimer’s Disease
1. Decline in Melatonin production and flattening of the melatonin rhythm has been a contributing factor for the early changes in the Alzheimer’s patients and is also responsible factor the upgradation of the oxidative stress. With regard to oxidative stress, prooxidant properties of the free amyloid-β molecule (Aβ) may be decisive, which is Fenton-reactive due to bound copper, and can, therefore, lead to hydroxyl radical-induced cell death. Initiation of Aβ increases the rise of flavor-enzyme and as a result rise in H2O2 in the intracellular level cause radical generation. Rise in Aβ protein have in fact shown to induce oxidative stress. Neurotrophin impairment activity on associated tyrosine kinase receptor is also an important factor in the pathology of Alzheimer’s disease2.
2. In many studies it has been postulated that there is decline in the level of melatonin in the plasma and cerebrospinal fluid in Alzheimer’s patients and the reduced level may serve as marker for the early diagnosis of Alzheimer’s patient.
3. Decreased melatonin receptor2 immunoreactivity and increased melatonin receptor1 immunoreactivity have been reported in the hippocampus of Alzheimer’s patients.
4. Disappearance of β1-adrenergic receptor mRNA and the activity and gene expression of monoamine oxidase were upregulated in Alzheimer’s disease patient. As a result there is dysregulation of noradrenergic innervations and depletion of serotonin level occurs. Serotonin is the precursor for melatonin synthesis and it might be a responsible factor for the loss of melatonin rhythm and reduced melatonin level in Alzheimer’s disease patient3.
5. Asymmetrical shape and structural polarity of the neurons are mainly maintained by cytoskeleton and these features are moreover essential for the maintenance of normal physiology. In neurodegenerative disorders there is disruption in the maintenance of normal cytoskeleton and also in neurotransmissions. Cytoskeleton rearrangement occurs with the help of melatonin. For neurite formation, melatonin receptor 1 is a responsible factor. Melatonin is a responsible factor to promote microtubule re-arrangement through Ca2+ antagonism, phosphorylation and organization of vimentin intermediate filaments via protein kinase C activation in N1E-115 cells. Deficiency of melatonin in Alzheimer’s patient reveals the fact that all the management activities described above leads to disruption pathologically in Alzheimer’s patient4.
For the better understanding of the disease more research procedures are going out for the better treatment and better upliftment of the human society.
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