one of the most common causes of dementia in old age, and the single most likely neuropathological to correlate of what had, until then, been known as senility³. At around the same time, two British teams independently reported that AD was associated with a severe loss of cholinergic markers in the cerebral cortex^4,5. These discoveries transformed AD from an obscure entity couched in the arcane nomenclature of plaques and tangles into a disease with a transmitter-based pathophysiology that could be approached in modern neuroscientific terms. The systematic biochemical investigation of the brains of Alzheimer’s disease (AD) patients started in the late 1960s and early 1970s. The hope was that a clearly defined abnormality would be identified, providing the basis for rational therapy analogous to L-DOPA treatment of Parkinson’s disease. In a few years of success seemed close with the identification of very substantial deficits in the enzyme responsible for the synthesis of acetylcholine-choline acetyltransferase (ChAT) - in the neocortex^4-6.

Pathophysiology:

Individuals with AD initially have trouble remembering recent events. They then become confused and forgetful, often repeating questions or getting lost while traveling to familiar places. Disorientation grows and memories of past event disappear, and episodes of paranoia, hallucination, or violent changes in mood may occur. As their minds continue to deteriorate, they lose their ability to read, write, talk, eat, or walk.

At an anatomical level, AD is characterized by gross diffuse atrophy of the brain and loss of neurons, neuronal processes and synapses in the cerebral cortex and certain subcortical regions. This results in gross atrophy of the affected regions, including degeneration in the temporal lobe and parietal lobe, and parts of the frontal cortex and cingulate gyrus⁷. Levels of the neurotransmitter acetylcholine are reduced. Levels of the neurotransmitters serotonin, norepinephrine, and somatostatin are also often reduced. Glutamate levels are usually elevated⁸.Formation of neurofibrillary tangles, oxidation and lipid peroxidation, glutamatergic excitotoxicity, inflammation and activation of the cascade of apoptotic cell death are considered secondary consequences of the generation and deposition of beta-amyloid. Cell dysfunction and cell death in nuclear groups of neurons responsible for maintenance of specific transmitter systems lead to deficits in acetylcholine, norepinephrine, and serotonin. Alternate hypotheses regarding the pathophysiology of AD place greater emphasis on the potential role of tau-protein abnormalities, heavy metals, vascular factors, or viral infections. Systematic biochemical investigation of AD has clearly demonstrated changes in other neurotransmitter system such as serotonin (5-HT) and noradrenaline that do not correlate strongly with the cognitive changes of AD^9-11. The cause of AD accounts due to changes in different genes. Mutation in three different genes (coding for presenilin-1, presenilin-2 and amyloid precursor protein) leads to early onset forms of AD in afflicted families but account for less than 1% of cases. Another gene, called APOE, codes for apolipoprotein E, a protein that helps transport cholesterol in the blood. People who have one or two copies of the e4 allele (form) of APOE have a much higher risk of developing AD and an earlier age of onset when compared with the people who have either the e2 or e3 allele¹².

Alzheimer's disease is definitely linked to the 1^st, 14^th, and 21^st chromosomes, but other linkages are controversial and not, as yet, confirmed. While some genes predisposing to AD have been identified, such as APOE4 on chromosome 19, sporadic AD also involves other risk and protective genes still awaiting confirmation¹³.

β-amyloid is a major histopathological hallmark of Alzheimer's disease (AD)¹⁴. It is associated with age-related cognitive decline, neurotoxicity, and the formation of neurofibrillary tangles (NFT)¹⁵. Therefore, several β-amyloid-lowering strategies are currently developed for clinical use. These include inhibition of the generation of amyloid β-peptide (Aβ) with β-a nd γ-secretase inhibitors, prevention of Aβ aggregation, and immunization against β-amyloid¹⁶. Both passive and active immunization of transgenic mice against β-amyloid can reverse neuropathology and improve pathologic learning and memory behaviors.¹⁷

Diagnosis:

The standard clinical criteria for the diagnosis of Alzheimer's disease were developed by the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer's disease and Related Disorders Association. Alzheimer’s disease is the most common form of dementia in the elderly. Dementia is commonly recognized with use of the criteria of the Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV)¹⁸ Alzheimer's disease is classified as into one of three diagnostic categories: definite Alzheimer's disease, probable Alzheimer's disease, and possible Alzheimer's disease. The diagnosis of definite Alzheimer's disease requires histopathologic confirmation of clinical features by postmortem examination. Diagnoses made from the findings of the postmortem examination correspond to antemortem diagnoses about 90% of the time¹⁹.

As part of the assessment of dementia, laboratory studies are necessary to identify causes of dementia and coexisting conditions that are common in the elderly. Thyroid-function tests and measurement of the serum vitamin B₁₂ level are required to identify specific alternative causes of dementia. A complete blood count; measurement of blood urea nitrogen, serum electrolyte, and blood glucose levels; and liver-function tests should be performed²⁰.Specialized laboratory studies such as a serologic test for syphilis, the erythrocyte sedimentation rate, a test for human immunodeficiency virus antibody, or screening for heavy metals are indicated when historical features or clinical circumstances suggest that infections, inflammatory diseases, or exposure to toxins may be contributing to the dementia. Neuroimaging plays an important role in the diagnosis of Alzheimer’s disease and is particularly helpful in excluding alternative causes of dementia. It is currently recommended that patients undergo structural imaging of the brain with computed tomography (CT) or magnetic resonance imaging at least once in the course of their dementia²⁰. Functional imaging with positron-emission tomography or single-photon-emission CT may be helpful in the differential diagnosis of disorders associated with dementia²¹.

Treatment:

There is currently no cure for Alzheimer's disease. Currently available medications offer relatively small symptomatic benefit for some patients but do not slow disease progression. The treatment of AD can be conceptualized as falling into two categories. The first approach relies on a replacement strategy that enhance the function of a deficient neurotransmitter system which are implicated in cognition and disrupted the illness .The efficacy of this strategy is measured by the amount of acute improvement in cognition and daily functioning .The aim of the second pharmacological approach is to interfere with the neurodegenerative process, thereby attenuating the patient’s clinical decline²².

Cholinergic approaches:

The rule of the cholinergic system in cognition and AD , including the following (1) Centrally active anticholinergic agent produce cognitive deficits; (2) Cholinergic neurotransmission modulates memory and learning; (3)Lesion of the central cholinergic system produce learning and memory impairments that can be reversed with cholinomimetic administration; and (4) Postmortem studies of patients with AD consistently document cholinergic cell loss in the nucleus of basalis of Meynert decreased concentrations of choline acetyl transferase and acetylcholinesterase, and correlation between these changes and the degree of cognitive impairment .

Cholinergic defect: According to the ‘cholinergic hypothesis of Alzheimer’s dementia’ the destruction of cholinergic neurons in the basal forebrain and the resulting deficit in central cholinergic transmission contribute substantially to the characteristic cognitive and non-cognitive symptoms observed in the patients²³. Reductions in the activities of choline acetyltransferase and AchE in brain tissues from Alzheimer’s disease patients were first reported in 1976 and 1977²⁴.

Inhibition of brain cholinesterase activity: After its release into the synaptic cleft the neurotransmitter acetylcholine is degraded rapidly by the hydrolytic activity of cholinesterase. In the human brain, the most prominent enzyme involved in acetylcholine hydrolysis is AChE. Recent evidence suggests that additionally, butyrylcholinesterase (BChE) can also hydrolyse acetylcholine in the brain and may play a role in cholinergic transmission²⁵. Donepezil and Galantamine are selective inhibitors of AChE, while rivastigmine also inhibits ButylChE, which accounts for 10% of the cholinesterase activity in normal human brain and appears to be predominantly associated with glia²⁶.

Systematic reviews of the available randomized, double-blind, placebo-controlled studies by the Cochrane Collaboration support the use of the three cholinesterase inhibitors rivastigmine donepezil and galantamine for treatment of mild to moderate Alzheimer’s disease^27,28. In a recent systematic review, however, the scientific basis for the recommendations of cholinesterase inhibitors for treatment of Alzheimer’s disease has been questioned²⁹.

Glutamate-mediated neurotoxicity: Glutamate excitotoxicity mediated through excessive activation of NMDA receptors is believed to play a role in the neuronal death observed in Alzheimer’s disease and other neurodegenerative conditions³⁰. Glutamate represents the main excitatory neurotransmitter in the central nervous system and a physiological level of glutamate-receptor activity is essential for normal brain function³¹. Glutamate receptors can be broadly divided into metabotropic glutamate receptors, which are coupled to G-proteins, and ionotropic receptors, which are ligand gated ion channels. On the basis of their sensitivity to synthetic agonists, the latter are classified into the NMDA, a-amino-3-hydroxy-5-methyl-4-isoxazole-propionate (AMPA) and kainate receptors³².

In Alzheimer’s disease, excessive activation of NMDA receptors is believed to cause increases in intracellular Ca²+which then triggers downstream events that ultimately lead to neurodegeneration³⁰. Consequently, NMDA-receptor antagonists may have a therapeutic potential for protecting neurons from glutamate-mediated neurotoxicity.

Potent NMDA-receptor antagonists like MK-801 or phencyclidine (PCP) were reported to produce psychotomimetic side effects, presumably due to interference with the physiological functions of NMDA glutamate receptors^31,32.A recent systematic review of double-blind, parallel group, placebo-controlled randomized trials of memantine in people with dementia published by the Cochrane Collaboration suggested a beneficial effect of memantine on cognitive function and functional decline in patients with moderate to severe Alzheimer’s disease, and on cognitive function in vascular dementia. The drug was reported to be well-tolerated³³.

Glycine site inhibitors: The glycine–B allosteric site on the NMDA receptor is positively modulating site. Glycine has been shown to act together with glutamate in the stimulation of the NMDA receptor. Antagonism of glycine modulatory site of the NMDA receptor could decrease neurotoxicity mediated by glutamate. One-hydroxy-3-amino-2-pyrrolidine (HA-966) and L-amino cyclobutane (ACB) appear to inhibit NMDA –specific binding and block NMDA response³⁴. Non NMDA antagonist also provide a potential therapeutic stratergy to decrease glutaminergic functioning and neurotoxicity. Antagonist of NMDA receptor include 2,3 –dihydroxy -6-nitro-7-sulfamoyl-benzo(F) quinoxaline(NQBX), 6,7–dinitroquinoxaline-2-3-dione(DNQX).

Neuroprotective approaches:³⁵

Mechanism-based therapeutic approaches targeting b-amyloid and tau pathologies :The characteristic neuropathological hallmarks of Alzheimer’s disease include neuritic plaques and NFTs³⁶. Neuritic plaques are extracellular lesions composed of a central core of aggregated amyloid- β peptide (Aβ) surrounded by dystrophic neuritis, activated microglia and reactive astrocytes³⁷. In 1984, Glenner and Wong first reported on the purification and partial amino acid sequence determination of the b-amyloid peptide from cerebrovascular amyloid associated with Alzheimer’s disease³⁸. NFTs are intracellular bundles of paired helical filaments and straight filaments 62³⁹.They are composed of tau protein⁴⁰ in an abnormally hyperphosphorylated form⁴¹.

Therapeutic strategies targeting β--amyloid:

The dominating hypothesis to explain the mechanisms leading to Alzheimer’s disease is the amyloid cascade hypothesis, which states that the Ab, a fragment of the amyloid precursor protein (APP), plays a central role in the pathogenesis. Aβ is produced proteolytically from APP by the so called b- and g secretases. It is believed that accumulation of b-amyloid (in particular of the Aβ-42 peptide) in the brain initiates a cascade of events that ultimately leads to neuronal dysfunction, neurodegeneration and dementia.⁴²The strongest argument supporting a causal role of b-amyloid in Alzheimer’s disease comes from the identification of mutations in the APP gene and in the genes for presenilin-1 and -2 (PS1and PS2 that are responsible for early-onset forms of familial Alzheimer’s disease (FAD)^43,44. By July 2006, 25 pathogenic mutations in APP, 155 in PS1 and 10 in PS2 were listed on the Alzheimer Disease & Fronto temporal Dementia⁴⁵.

According to the amyloid cascade hypothesis novel therapeutic strategies that lower Aβ- levels or prevent the formation of the presumed neurotoxin oligomeric A β- species are predicted to stop or slow down the progession of neurodegeneration and dementia in Alzheimer’s disease.

Modulation of Aβ- production:

Aβ- peptides are proteolytic fragments of the APP, a large integral membrane protein that is composed of a signal sequence, a large extra-membranous region, a single transmembrane domain and a small cytosolic C-terminal tail⁴⁶. Post-translational modifications of APP include phosphorylation, tyrosine-sulphation and N-and O-linked glycosylations⁴⁷. Aβ-is generated from APP by sequential cleavages by two proteases termed b- and g- secretase.

Several pharmaceutical companies have actively searched for small molecule compounds that can reduce Ab production by affecting one of these targets. The finding that certain non-steroidal anti-inflammatory drugs (NSAIDs) can preferentially reduce the generation of the highly amyloidogenic Aβ-42 species without affecting Notch cleavage indicates the existence of a g-secretase modulating mechanism as a potential drug target that may allow for lowering Aβ-42 levels without inducing potential side effects related to complete inhibition of g-secretase.⁴⁸

Inhibition of Aβ--aggregation: Preventing the formation of the presumed toxic oligomeric aggregates of Aβ-by small molecules represents another promising approach for the development of novel and causal therapeutics for treating Alzheimer’s disease. Metal ions like Cu²+and Zn²+may be involved in the mediation of Ab aggregation and toxicity⁴⁹. A significant decrease in brain Aβ- deposition in APP-transgenic mice was observed after 9 weeks treatment with clioquinol, an antibiotic and Cu/Zn chelator that crosses the blood–brain barrier⁵⁰.

Aβ -immunotherapy: In a landmark paper in 1999 Dale Schenk and co-workers described that immunization with Ab attenuates the Alzheimer’s disease-like pathology in a transgenic mouse model of Alzheimer’s disease.⁵¹ Using peripheral antibody administration the same group provided direct evidence that Aβ antibodies are sufficient to reduce the amyloid deposition⁵². Aβ immunization was shown to also reduce various aspects of the amyloid- associated pathology including neuritic dystrophy and synaptic degeneration as well as early tau accumulation⁵³.

Therapeutic strategies targeting tau hyperphosphorylation and neurofibrillary degeneration:

Neurofibrillary lesions made up from aggregated hyperphosphorylated forms of the microtubule-associated protein tau represent a second defining neuropathological feature of Alzheimer’s disease. The pathological hyperphosphorylation of tau, which can be visualized by immunochemical methods, is an early event in the development of Alzheimer’s disease-related neurofibrillary changes⁵⁴. Phosphorylation of tau regulates its ability to promote microtubule assembly and abnormal hyperphosphorylation interferes with its normal biological function by decreasing tau’s ability to bind to, and to stabilize, microtubules⁵⁵.

Under pathological conditions, an imbalance of kinase and phosphates activities may lead to aberrant hyperphosphorylation of tau resulting in its detachment from microtubules, breakdown of the microtubule network, disturbance of axonal transport and ultimately neurodegeneration. The inhibition of tau-related neurofibrillary degeneration represents a highly promising approach in search for novel therapies for Alzheimer’s disease and related tauopathies. This may be achieved by targeting one or more tau kinase(s), by increasing the activity of protein phosphatase (PP)-2A or by inhibition of the presumed toxic properties of pathological tau proteins⁵⁶.

Inhibition of tau kinases:

More than 30 Phosphorylation sites on tau protein have been described and numerous prolines directed and non-proline directed kinases were shown to be able to phosphorylate tau protein in vitro. These include glycogen synthase kinase 3-b (GSK3-b), cdc2-like kinase (cdk5), and extracellular signal-regulating kinase-2 (ERK2), microtubule-affinity-regulating kinase (MARK), protein kinase A (PKA), members of the stress-activated protein kinase (SAPK) family, Ca²+/ calmodulin-dependent kinase II and casein kinases I and II⁵⁷.

Markers of neuroinflammation including activated microglia and astrocytes, complement components and inflammatory cytokines are typically observed in association with Alzheimer’s disease neuropathology⁵⁸. Observational retrospective and prospective studies indicated that the long-term use of NSAIDs may have a preventive effect against the development of Alzheimer’s disease suggesting that neuro-inflammation may contribute to the neurodegeneration⁵⁹.

Cholesterol metabolism appears to play an important role in the biology of APP and possibly also in the pathological processes leading to Alzheimer’s disease. APP processing and Ab production are sensitive to cholesterol levels⁶⁰.The activities of both, b- and g-secretase, were shown to be inhibited by lowering cholesterol in cultured neurons⁶¹. In humans, lovastatin was reported to reduce serum Ab concentration in a dose-dependent manner⁶². A recent meta-analysis did not reveal Alzheimer’s disease associated polymorphisms in cholesterol-related genes other than APOE and it was therefore concluded that the link between Alzheimer’s disease and APOE4 was probably not directly related to cholesterol⁶³.

CONCLUSION:

In Alzheimer’s disease state of dementia proceeded as mild cognitive impairments. The treatment requires accurate diagnosis and understanding of pathological condition where currently developed therapy like β--amyloid lowering agent, modulation of β- amyloid protection and inhibition of amyloid β--aggregation etc. is applicable. This therapy would be of particular utility if the disease is diagnosed in mild stage so the substantial amount of day–to-day functioning is still preserved. Cholinesterase inhibitor therapy is the most developed area of research and the only FDA-approved treatment. Yet it is the challenge before scientist to find most effective treatment for cognitive deterioration observed in patients with Alzheimer disease.

REFERENCES:

1) McKhann G, Drachman DA, Folstein M, Katzman R, Price D, and Stadlan EM. Clinical diagnosis of Alzheimer’s disease. Neurology 1984; 34: 939–944.

2) Petersen RC, Smith GE, Waring SC, Ivnik R, Tangalos, EG, and Kokmen, E. Mild cognitive impairment. Clinical characterization and outcome. Arch. Neurol. 1999;56: 303–308.

3) Katzman R. The prevalence and malignancy of Alzheimer disease. Arch. Neurol. 1976; 33: 217–218.

4) Bowen DM, Smith CB, White P, and Davison AN. Neurotransmitter-related enzymes and indices of hypoxia in senile dementia and other a biotrophies. Brain. 1976;99: 459–496

5) Davies P and Maloney AJF. Selective loss of central cholinergic neurons in Alzheimer’s disease. Lancet.1976; 2: 1943.

6) Perry EK. Gibson PH, Blessed G, Perry RH, and Tomlinson BE. Neurotransmitter enzyme abnormalities in senile dementia. Choline acetyltransferase and glutamic acid decarboxylase activities in necroscopy brain tissue. J.Neurol.Sci. 1977 ; 34:247-265.

7) Wenk GL. Neuropathologic Changes in Alzheimer’s disease. J.Clin.Psychiatry. 2003; 64(9): 7-10.

8) Lipton SA. Paradigm shift in neuroprotection by NMDA receptor blockade: memantine and beyond. Nat. Rev. Drug Discovery .2006; 5(2): 160-170.

9) Palmer AM, Wilock GK, Esiri MM, Francis, PT and Bowen DM. Monoaminergic innervation of the frontal and temporal lobes in alzheimer’s disease. Brain Res. 1987; 401:231-238.

10) Leake A, Moore PB, Leitch M., Ayre K, Perry RH, Ince PG, Ferrier IN. The serotonergic system in Alzheimer’s disease and normal neocortical post mortem brain: neurochemical and clinical correlates.Neurol.Psychar.Brain Res. 1993;2:53-59.

11) Yates CM, Simpson J, Gordon A, Maloney AFJ, Allison Y, Ritchie IM, and Urquhart A. Catecholamine and cholinergic enzymes in pre senile and senile Alzheimer type dementia and Down’s syndrome. Brain Res. 1983; 280: 119-126.

12) Naslund J, Haroutunian V, Mohs R, Davis KL, Davies P. Greengard P. and Buxbaum, JD. Correlation between elevated levels of amyloid beta-peptide in the brain and cognitive decline. JAMA.2000; 283:1571–1577.

13) Chen GQ, Chen KS, Knox J, Inglis J, Bernard A, Martin SJ, Justice A, McConlogue L, Games D, Freedman SB and Morris RG. A learning deficit related to age and β-amyloid plaques in a mouse model of Alzheimer's disease, Nature. 2000;408:975–979

14) The National Institute on Aging, and Reagan Institute Working Group on Diagnostic Criteria for the Neuropathological Assessment of Alzheimer's disease. In Consensus recommendations for the post-mortem diagnosis of Alzheimer's disease. Neurobiol. Aging. 1997; 18: S1–S2.

15) Lewis J, Dickson DW, Lin WL, Chisholm L, Corral A, Jones G, Yen SH, Sahara N, Skipper L and Yager D et al., Enhanced neurofibrillary degeneration in transgenic mice expressing mutant tau and APP, Science. 2001; 293:1487–1491.

16) Citron M. Alzheimer's disease: Treatments in discovery and development, Nat. Neurosci. 2002; 5:1055–1057.

17) DeMattos RB, Bales KR, Cummins DJ, Dodart JC, Paul SM and Holtzman DM, Peripheral anti-Aβ antibody alters CNS and plasma Aβ clearance and decreases brain Aβ burden in a mouse model of Alzheimer's disease, Proc. Natl. Acad. Sci. USA.2001; 98: 8850–8855.

18) Diagnostic and statistical manual of mental disorders, 4^th ed. DSM-IV. Washington, D.C.: American Psychiatric Association, 1994.

19) Kawas CH. Early Alzheimer’s disease. N Engl J Med 2003; 349:1056-63.

20) Knopman DS, DeKosky ST, and Cummings JL, et al. Practice parameter: Diagnosis of dementia (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology. Neurology 2001; 56:1143-53.

21) Silverman DH, Small GW, Chang CY, et al. Positron emission tomography in evaluation of dementia: regional brain metabolism and long-term outcome. JAMA 2001; 286:2120-7.

22) The American Association for Geriatric Psychiatry published a consensus statement on Alzheimer's treatment in 2006.

23) Cummings JL, Back C. The cholinergic hypothesis of neuropsychiatric symptoms in Alzheimer’s disease. Am J Geriatr Psychiatry. 1998; 6: S64–78.

24) Perry EK, Perry RH, Blessed G, Tomlinson BE. Necropsy evidence of central cholinergic deficits in senile dementia. Lancet 1977; 1: 189.

25) Mesulam MM, Guillozet A, Shaw P, Levey A, Duysen EG, Lockridge O. Acetyl cholinesterase knockouts establish central cholinergic pathways and can use butyrylcholinesterase to hydrolyze acetylcholine. Neuroscience 2002b; 110: 627–39.

26) Scarpioi E, Scheltens P, Feldman H. Treatment of Alzheimer’s disease: Current status and new perspectives. Lancet Neurol 2003; 2: 539–47.

27) Loy C, Schneider L. Galantamine for Alzheimer’s disease. Cochrane Database Syst Rev 2004, CD001747.

28) Birks JS, Harvey R. Donepezil for dementia due to Alzheimer’s disease. Cochrane Database Syst. Rev 2003; CD001190.

29) Kaduszkiewicz H, Zimmermann T, Beck-Bornholdt HP, Van den Bussche H. Cholinesterase inhibitors for patients with Alzheimer’s disease: Systematic review of randomized clinical trials. BMJ 2005; 331: 321–7.

30) Hynd MR, Scott HL, Dodd PR. Glutamate-mediated excitotoxicity and neurodegeneration in Alzheimer’s disease. Neurochem Int. 2004; 45: 583–95.

31) Kornhuber J, Weller M. Psychotogenicity and N-methyl-D-aspartate receptor antagonism: implications for neuroprotective pharmacotherapy. Biol Psychiatry 1997; 41: 135–44.

32) Javitt DC. Glutamate as a therapeutic target in psychi atric disorders. Mol Psychiatry 2004; 9: 984-97–979.

33) Areosa Sastre A, Sherriff F, McShane R. Memantine for dementia (Cochrane Review). Cochrane Database Syst Rev 2005; 2.

34) Hood WF, Sun ET, Compton RP, Monahan JB. 1-aminocyclo-butane 1-carboxylase (ACBC): A specific antagonist of the N-methyl- D-aspartate receptor coupled glycine receptor. Eur.J.Pharmacol. 1989;161:281-282.

35) Honore T, Davies SN, Drejer J, Fletcher EJ, Jacobsen P, Lodge D, and Nielsen FE. Quinoxalinediones: potent competitive non NMDA glutamate receptor antagonist.Science.1988; 241:701-703.

36) Alzheimer A. U¨ ber eigenartige Krankheitsfa¨lle des spa¨teren Alters. Zeitschrift fu¨r die Gesamte Neurologie und Psychiatrie 1911; 4: 356–85.

37) Selkoe DJ. The molecular pathology of Alzheimer’s disease. Neuron.1991; 6: 487–98.

38) Glenner GG, Wong CW. Alzheimer’s disease: Initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem Biophys Res Commun 1984; 120: 885–90.

39) Terry RD. The fine structure of neurofibrillary tangles in Alzheimer’s disease. J Neuropathol Exp Neurol 1963; 22: 629–42.

40) Wischik CM, Novak M, Thogersen HC, Edwards PC, Runswick MJ, Jakes R, et al. Isolation of a fragment of tau derived from the core of the paired helical filament of Alzheimer disease. Proc Natl Acad Sci USA 1988; 85: 4506–10.

41) Sergeant N, Bussiere T, Vermersch P, Lejeune JP, Delacourte A. Isoelectric point differentiates PHF-tau from biopsy-derived human brain tau proteins. Neuroreport 1995; 6: 2217–20.

42) Hardy J, Selkoe DJ. The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 2002; 297: 353–6.

43) Murrell J, Farlow M, Ghetti B, Benson MD. A. mutation in the amyloid precursor protein associated with hereditary Alzheimer’s disease. Science 1991; 254: 97–9.

44) Sherrington R, Rogaev EI, Liang Y, Rogaeva EA, Levesque G, Ikeda M, et al. Cloning of a gene bearing missense mutations in early-onset familial Alzheimer’s disease. Nature 1995; 375: 754–60.

45) Cruts M, Rademakers R. Alzheimer Disease & Front temporal Dementia Mutation Database. Available at: http://www.molgen.ua.ac.be/ AD Mutations /. Accessed 2006.

46) Kang J, Lemaire HG, Unterbeck A, Salbaum JM, Masters CL, Grzeschik KH, et al. The precursor of Alzheimer’s disease amyloid A4 protein resembles a cell-surface receptor. Nature 1987; 325: 733–6.

47) Oltersdorf T, Ward PJ, Henriksson T, Beattie EC, Neve R, Lieberburg I, et al. The Alzheimer amyloid precursor protein. Identification of a stable intermediate in the biosynthetic/ degradative pathway. J Biol Chem 1990; 265: 4492–7.

48) Weggen S, Eriksen JL, Das P, Sagi SA, Wang R, Pietrzik CU, et al. A subset of NSAIDs lower amyloidogenic A beta 42 independently of cyclooxygenase activity. Nature 2001; 414: 212–6.

49) Atwood CS, Moir RD, Huang X, Scarpa RC, Bacarra NM, Romano DM, et al. Dramatic aggregation of Alzheimer A beta by Cu (II) is induced by conditions representing physiological acidosis. J Biol Chem 1998; 273: 12817–26.

50) Cherny RA, Atwood CS, Xilinas ME, Gray DN, Jones WD, McLean CA, et al. Treatment with a copper-zinc chelator markedly and rapidly inhibits beta-amyloid accumulation in Alzheimer’s disease transgenic mice. Neuron 2001; 30: 665–76.

51) Schenk D, Barbour R, Dunn W, Gordon G, Grajeda H, Guido T, et al. Immunization with amyloid-beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature 1999; 400: 173–7.

52) Bard F, Barbour R, Cannon C, Carretto R, Fox M, Games D, et al. Epitope and isotype specificities of antibodies to beta-amyloid peptide for protection against Alzheimer’s disease-like neuropathology. Proc Natl Acad Sci. USA 2003; 100: 2023–8.

53) Buttini M, Masliah E, Barbour R, Grajeda H, Motter R, Johnson-Wood K, et al. Beta-amyloid immunotherapy prevents synaptic degeneration in a mouse model of Alzheimer’s disease. J Neurosci. 2005; 25: 9096–101

54) Braak H, Braak E. Staging of Alzheimer’s disease-related neurofibrillary changes. Neurobiol Aging. 1995; 16: 271–84.

55) Alonso AC, Zaidi T, Grundke-Iqbal I, Iqbal K. Role of abnormally phosphorylated tau in the breakdown of microtubules in Alzheimer disease. Proc Natl Acad Sci USA 1994; 91: 5562–6

56) Mandelkow EM, Mandelkow E. Tau in Alzheimer’s disease. Trends Cell Biol 1998; 8: 425–7.

57) Johnson GVV, Hartigan JA. Tau protein in normal and Alzheimer’s disease brain: an update. Alzheimer’s Dis Rev 1998; 3:125–141.

58) Tuppo EE, Arias HR. The role of inflammation in Alzheimer’s disease. Int J Biochem Cell Biol 2005; 37: 289–305.

59) Szekely CA, Thorne JE, Zandi PP, Ek M, Messias E, Breitner JC, et al. Nonsteroidal anti-inflammatory drugs for the prevention of Alzheimer’s disease: a systematic review. Neuroepidemiology. 2004; 23: 159–69.

60) Simons M, Keller P, De Strooper B, Beyreuther K, Dotti CG, Simons K. Cholesterol depletion inhibits the generation of beta-amyloid in hippocampal neurons. Proc Natl Acad Sci USA 1998; 95: 6460–4.

61) Cordy JM, Hussain I, Dingwall C, Hooper NM, Turner AJ. Exclusively targeting beta-secretase to lipid rafts by GPI-anchor addition up-regulates beta-site processing of the amyloid precursor protein. Proc Natl Acad Sci USA 2003; 100: 11735–40.

62) Wolozin B. Cholesterol and the biology of Alzheimer’s disease. Neuron 2004; 41: 7–10.

63) Wolozin B, Manger J, Bryant R, Cordy J, Green RC, McKee A. Re-assessing the relationship between cholesterol, statins and Alzheimer’s disease. Acta Neurol Scand Suppl 2006; 185: 63–70

Received on 16.06.2010

Accepted on 10.07.2010

Research J. Pharmacology and Pharmacodynamics. 2(4): July-August 2010, 268-273