Degenerative Diseases Are The Diseases Of Grey Matter Biology Essay


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Progressive changes in molecular environment of neurons and neurodegeneration has its implication in psychological functioning. Degenerative diseases are the diseases of grey matter characterized by the progressive loss of neurons which is associated with secondary changes in white matter of brain .The pattern of neuronal loss is selective , affecting one or more group of neurons leaving others intact. They arise without any clear inciting event in a event in a patient without previous neurologic deficits.

The major critical degenerative diseases are Alzheimer's disease and Pick disease. Their clinical manifestation is seemed to be "dementia".

Dementia is the progressive loss of cognition independent of the state of attention resulting from diseases of the brain. It may be due to.,

Therapeutic drug use (e.g. Atropine, Phenytoin,etc.,)

Metabolic systemic disorders (e.g. Acid-base disorders, hypo - ,hyperglycemia , haematological disorders ,Pulmonary insufficiency, Hypopituitarism, Cardiac dysfunction, Hepatolenticular degeneration)

Intracranial disorders (e.g. cerebrovascular insufficiency, chronic meningitis or encephalitis, neurosyphilis, HIV, Epilepsy,tumor,abscess,subdural hematomas, multiple sclerosis, normal pressure hydrocephalus)

Deficiency states (e.g. vitamin B 12 deficiency, folate deficiency, niacin or pellagra)

Collagen - vascular disorders : Systemic lupus erythematosus, temporal arteritis, sarcoidosis, Behcet's syndrome)

Exogenous intoxication: (e.g. Alcohol, Carbon monoxide, organophosphates, toluene, trichloroethylene , carbon disulfide, lead, mercury, arsenic, thallium, manganese)

Dementia is not part of normal aging and always represents a pathologic process. The present study investigates on the Alzheimer's disease where dementia is one of the clinical manifestations.

Alzheimer's disease - the most common form of dementia caused by progressive neuronal degeneration with pathological features showing the presence of amyloid plaques and neurofibrillary tangles, primarily affecting middle-aged and elderly individuals in whom it is cause of 70 percent of cases of dementia.


The accurate etiology of Alzheimer's disease is unknown. The salient pathological features are the presence of amyloid plaques and neurofibrillary tangles. The "amyloid cascade hypothesis" is mainly investigated by the researchers and there is still the search for cause of Alzheimer's disease. The amyloid cascade hypothesis is supported by the study of early-onset inherited (genetic) Alzheimer's disease. In early-onset disease, Mutations associated with Alzheimer's disease have been found in about half of the patients. The mutation leads to increased formation in the brain of a particular form of a small protein fragment called A-Beta (Aβ). In the majority of sporadic (for example, non-inherited) cases of Alzheimer's disease (these make up the vast majority of all cases of Alzheimer's disease) there is too little removal of Aβ protein rather than its increased production. The past and ongoing researches are focusing on the ways to prevent or slow down Alzheimer's disease to decrease the amount of Aβ in the brain, where one of the probable causative known.


Physicians keenly observe the following signs for complete evaluation

Loss of memory

Difficulty in familiar tasks performance.

Language problem

Disorientation in time and place

Decreased judgment

Abstract thinking problem

Misplacing things

Mood or behaviour changes

Personality changes

Loss of initiative.


Early stage:

Memory problems initially dismiss as "a normal part of aging" are to be the first stages of Alzheimer's disease. Short-term memory is common, early in the course of Alzheimer's disease.

Mild personality changes, such as less spontaneity, apathy, and a tendency to withdraw from social interactions, may occur early in the illness.

As the disease progresses:

Problems in intellectual functions develop.

Disturbances in behaviour and appearance e.g. agitation, irritability, quarrelsomeness, and a diminishing ability to dress appropriately.

Later in the course of the disorder:

Affected individuals may become confused or disoriented

Unable to define their place where they live or to name a place

Patients may wander

Unable to engage in conversation


Lose bladder and bowel control.

Final stages of the disease:

Patient may become totally incapable of caring for themselves. Death can then follow, perhaps from pneumonia or some other problem that occurs in very severe deteriorated conditions. Persons in their later age in life more often die from other illnesses (e.g. heart disease) rather than due to Alzheimer's disease.


Early onset AD

Late onset AD

Familial AD

Early onset Alzheimer's: (EOAD)

It is a rare form of AD affecting the people before age 65. This type is seen in less than 10% of all AD patients. They experiences premature aging, so those people with Down syndrome are specifically at risk of this type. It is linked with a genetic defect on chromosome 14, where this is not the case in late onset AD. These chromosomal defects can undergo mutation of three genes namely presenilin1, presenilin2, and amyloid precursor protein. Certain conditions were prevalent in AD. Such a condition called myoclonus which causes muscle twitching and spasms is much more common in people with early onset AD.

Late onset:

It is the most common type affecting about 90% of all those with Alzheimer's. Persons with over the age of 65 suffering from it. Late-onset Alzheimer's doubles every five years after the age of 65 and not hereditary. It is also known as "sporadic Alzheimer's" because it can affect any elderly person. On average people live roughly eight to ten years after diagnosis. Sometimes with sporadic Alzheimer's, because it affects people so late in life, if they are associated with other diseases their life time reduces and lead to death.E4 type of gene is responsible for producing the apo lipoprotein.

Familial Alzheimer's:

Familial Alzheimer's is entirely inherited. The affected families may show their inheritance to their of springs at least of two generations. It is rare, less than 1% of cases of Alzheimer's disease have FAD. Histological examination shows familial AD is indistinguishable from other forms of the disease. Amyloid deposits can be seen in the sections of brain tissue. Amyloid protein forms plaques and neurofibrillary tangles that progress through the memory centers of the brain. The uniqueness of plaque is rare or uncharacteristic of AD. This occurs when the mutation in one of the genes that creates a functional, but malformed protein instead of the ineffective gene products that usually results from mutations. Mutation in different genes like the amyloid precursor protein (APP) gene and the presenilin 1 and 2 (PSEN1 and PSEN2) genes have been discovered in families with early-onset familial disease. The products of these genes interact with the proteins in molecular level and involve in signalling process within and between cells.


The symptomatic treatment of Alzheimer's has been the present management. The cholinesterase inhibitors of different classes are of gaining importance. A major approach to the treatment of AD has involved attempts to augment the cholinergic function of the brain (Johnston, 1992). An early approach was the use of precursors of acetylcholine synthesis, such as choline chloride and phosphatidyl choline (lecithin).Although these supplements generally are well tolerated, randomized trials have failed to demonstrate any clinically significant efficacy.

A somewhat more successful strategy has been the use of inhibitors of acetyl cholinesterase (AChE), the catabolic enzyme for acetylcholine. Physostigmine, a rapidly acting, reversible AChE inhibitor, produces improved responses in animal models of learning, and some studies have demonstrated mild transitory improvement in memory following physostigmine treatment in patients with AD. The use of physostigmine has been limited because of its short half-life and tendency to produce symptoms of systemic cholinergic excess at therapeutic doses. Four inhibitors of AChE currently are approved by the FDA for treatment of Alzheimer's disease: Tacrine, donepzil, Rivastigmine , and Galantamine(Mayeux and Sano, 1999)

Tacrine is a potent centrally acting inhibitor of AchE (Freeman and Dawson, 1991). Studies of oral tacrine in combination with lecithin have confirmed that there is indeed an effect of tacrine on some measures of memory performance, but the magnitude of improvement observed with the combination of lecithin and tacrine is modest at best (Chatellier and Lacombelz, 1990). The side effects of tacrine often are significant and dose-limiting; abdominal cramping, anorexia, nausea, vomiting, and diarrhoea are observed in up to one-third of patients receiving therapeutic doses, and elevations of serum transaminases are observed in up to 50% of those treated. Because of significant side effects, tacrine are not used widely clinically.

Donepezil is a selective inhibitor of AChE in the CNS with little effect on AChE in peripheral tissues. It produces modest improvements in cognitive scores in Alzheimer's disease patients (Rogers and Friedhoff, 1998) and has a long half-life, allowing once-daily dosing.

Rivastigmine and Galantamine are dosed twice daily and produce a similar degree of cognitive improvement. Adverse effects associated with Donepzil, Rivastigmine and Galantamine are similar in character but generally less frequent and less severe than those observed with tacrine; they include nausea, diarrhoea, vomiting, and insomnia. Donepzil, Rivastigmine, and Galantamine are not associated with the hepato-toxicity.

An alternative strategy for the treatment of AD is the use of the NMDA glutamate-receptor antagonist Memantine. Memantine produces a use-dependent blockade of NMDA receptors. In patients with moderate to severe AD, use of memantine is associated

with a reduced rate of clinical deterioration (Reisberg et al. , 2003) .Whether this is due to a true disease modifying effect, possibly reduced excitotoxicity, or is a symptomatic effect of the drug is unclear. Adverse effects of memantine usually are mild and reversible and may include headache or dizziness.

At present Dipeptidylpeptidase-9(DPP-9) and BACE enzymes are in current investigation for the treatment of AD.

The disease management of present scenario focuses on AchE inhibition and new memories. The existing Ach molecules are prevented from degradation and there by act on intact Ach receptors by the use of AchE inhibitors.


Acetyl choline esterase is an enzyme involved in lysis of acetyl group and choline group in acetyl choline (CH3-CH2-(CO)2-CH2-CH2-N-(CH3)3. Acetylcholine (Ach) is a neurotransmitter in both the peripheral nervous system (PNS) and central nervous system is one of many neurotransmitters in the autonomic nervous system and the only neurotransmitter used in the motor division of the somatic nervous system (Sensory neurons use glutamate and various peptides at their synapses.)

Synthesis and degradation:

Acetylcholine is synthesized in certain neurons by the enzyme choline acetyl transferase from the compounds choline and acetyl Co-A.

The enzyme acetyl cholinesterase converts acetylcholine into the inactive metabolite choline and acetate. This enzyme is abundant in the synaptic cleft, and its role in rapidly clearing free acetylcholine from the synapse is essential for proper muscle function. Certain neurotoxins work by inhibiting acetyl cholinesterase, thus leading to excess acetylcholine at the neuromuscular junction, thus causing paralysis of the muscles needed for breathing and stopping the beating of the heart.


File:Acetylcholine.svg File:ACh-stick.png

Fig: Acetyl choline structure A) normal view B) stick model

Acetylcholine is also the principal neurotransmitter in all autonomic ganglia and the Post Synaptic Parasympathetic neuron and causes the release of the acetyl choline from the synaptic vesicles thereby innervate the neuromuscular junction and in pre synaptic Sympathetic nervous system it causes the release of acetyl choline and causes the innervation of the post synaptic nerve fibres and causes the release of nor adrenaline.

On release of acetylcholine from the receptor site they causes the contraction of the muscle fibres. If this enzyme has been degraded by acetyl choline esterases then depletion of Ach leads to various disease and disorders like Myasthenia gravis,Alzhiemer's disease, and Glaucoma. The most prevalant in western and some of the asian races is alzhiemers disease.

The thorough study on molecular basis of AchE and pathological neuronal degeneration paves the way for treating AD.


AchE exists in two general classes of molecular forms, simple homomeric oligomers of catalytic subunits (i.e. monomers, dimers, and tetramers) and heteromeric associations of catalytic subunits with structural subunits. The homomeric forms are found as soluble species in the cell, presumably destined for export, or associated with outer membrane of the cell through either an intrinsic hydrophobic amino acids sequence or an attached glycophospholipid. One heterologous form, largely found in neuronal synapses, is a tetramer of catalytic subunits disulfide-linked to a 20,000-dalton lipid linked sub unit. Similar to the glycophospholipid-attached form, it is found in the outer surface of the cell membrane. The other consists of tetramers of catalytic subunits, di sulphide linked to each of three strands of collagen-like structural subunit. This molecular species, whose molecular mass approaches 106 Daltons, is associated with the basal lamina of junctional areas of skeletal muscle.

File:PBB Protein ACHE image.jpg

Fig: 3-dimensional structural image (ribbon-like) of Acetylcholine esterase

The 3-dimensional structure of acetyl choline esterase shows the active centre to be nearly centerosymmetric to each subunit and reside at the base of a narrow gorge about 20Ȧ in depth (Sussman et al., 1995). At the base of the gorge lie the residues of the catalytic triad: serine 203, histidine 447, and glutamate 334.

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Fig: Active site gorge of AchE with serine 203, histidine 447 & glutamate 334 (source: Goodman & Gillman,the pharmacological basis of therapeutics 11th edition)

The catalytic mechanism resembles that of other hydrolases, where the serine hydroxyl group is rendered highly nucleophilic through a charge- relay system involving the carboxyl from glutamate, the Imidazole on the histidine, and the hydroxyl of the serine. During the enzymatic attack of the, an ester with trigonal geometry, a tetrahedral intermediate between enzyme and substrate is formed that collapse to an acyl enzyme conjugate with the concomitant release of choline. The acetyl enzyme is very labile to hydrolysis, which results in the formation of acetate and active enzyme. AchE is one of the most efficient enzymes known and has the capacity to hydrolyse 6 x 105 Ach molecules per molecule of enzyme per minute; this yields a turnover time of 150 microseconds.

Fig: The binding sites of AChE based upon biochemical studies performed prior to determination of the 3D structure. ES -esteratic site; AS-anionic substrate binding site; ACS-aromatic cation binding site; PAS-peripheral anionic binding site.

In the diagram, the hatched areas represent putative hydrophobic binding regions. ACh is shown spanning the esteratic and anionic sites of the catalytic center. Imidazole and hydroxyl side chains of His and Ser are shown within the esteratic site. Within the anionic site (COO−) n represents 6-9 putative negative charges.


AD is characterized by marked atrophy of the cerebral cortex and loss of cortical and sub cortical neurons. The pathological hallmarks of AD are senile plaques, which are spherical accumulations of the protein b-amyloid accompanied by degenerating neuronal processes, and neurofibrillary tangles, composed of paired helical filaments and other proteins (Arnold et al., 1991; Braak and Braak ,1994).


Fig: Formation of amyloid plaques from amyloid precursor protein (APP) by gamma secretase and beta secretase at the respective cleavage site of APP.

Although small numbers of senile plaques and neurofibrillary tangles can be observed in intellectually normal individuals, they are far more abundant in patients with AD, and the abundance of tangles is roughly proportional to the severity of cognitive impairment. In advanced AD, senile plaques and neurofibrillary tangles are numerous and most abundant in the hippocampus and associative regions of the cortex, whereas areas such as the visual and motor cortices are relatively spared. This corresponds to the clinical features of marked impairment of memory and abstract reasoning, with preservation of vision and movement. The factor underlying the selective vulnerability of particular cortical neurons to the pathology of the effect is unknown.

The neurochemical disturbances that arise in AD have been studied intensively (Johnston, 1992). Direct analysis of neurotransmitter content in the cerebral cortex shows a reduction of many transmitter substances that parallels neuronal loss; there is a striking and disproportionate deficiency of acetylcholine. The anatomical basis of the cholinergic deficit is the atrophy and degeneration of subcortical cholinergic neurons, particularly those in the forebrain (nucleus basalis of Meynert), that provide cholinergic innervations to the whole cerebral cortex. The selective deficiency of acetylcholine as well as the observation that central cholinergic antagonists such as atropine can induce a confusional state that bears some resemblance to the dementia of AD, has given rise to the "cholinergic hypothesis," which proposes that a deficiency of acetylcholine is critical in the genesis of the symptoms of AD (Perry 1986) Although the conceptualization of AD as a "cholinergic deficiency syndrome" in parallel with the "dopaminergic deficiency syndrome" of PD provides a useful framework, it is important to note that the deficit in AD is far more complex, involving 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 input.

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Fig: Neuronal pathways and signalling of parasympathetic nerve fibres involved in amyloid plaques accumulation and formation.

Role of β-Amyloid:

The presence of aggregates of β--amyloid is a constant feature of AD. Until recently, it was not clear whether the amyloid protein was causally linked to the disease process or merely a by-product of neuronal death. The application of molecular genetics has shed some light on this question.

β-amyloid from affected brains and found to be a short polypeptide of 42 to 43 amino acids. This information led to cloning of amyloid precursor protein (APP), a much larger protein of more than 700 amino acids, which is expressed widely by neurons throughout the brain in normal individuals as well as in those with AD. The function of APP is unknown, although the structural features of the protein suggest that it may serve as a cell surface receptor for an as-yet-unidentified ligand. The production of β-amyloid from APP appears to result from abnormal proteolytic cleavage of APP by the b-site APP-cleaving enzyme BACE. This may be an important target of future therapies (Vassar et al)

Analysis of APP gene structure in pedigrees exhibiting autosomal dominant inheritance of AD has shown that in some families, mutations of the β-amyloid-forming region of APP are present, whereas in others, mutations of proteins involved in the processing of APP are implicated (Selkoe, 2002).

These results suggest that it is possible for abnormalities in APP or its processing to cause AD. The vast majority of cases of AD, however, are not familial, and structural abnormality of APP or related proteins has not been observed consistently in these sporadic cases of AD.As noted earlier, common alleles of the Apo E protein have been found to influence the probability of developing AD. Many investigators believe that modifying the metabolism of APP might alter the course of AD in both familial and sporadic cases, but no clinically practical strategies have been developed.

The molecular level target on BACE(beta secretase) ,gamma secretase, are the enzymes under the research for the prevention of neuronal loss which is involved in the amyloid cascade hypothesis. Where the drugs developed for clinical trials on the Alzheimer's disease at present is focussing on these secretase enzymes. The future therapies will rely on targeting the secretase enzymes rather than going for cholinesterase inhibitors which is given for the formation of new memories.

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