{"id":841,"date":"2018-07-18T21:53:48","date_gmt":"2018-07-19T02:53:48","guid":{"rendered":"http:\/\/www.bocsci.com\/blog\/?p=841"},"modified":"2018-07-27T02:23:13","modified_gmt":"2018-07-27T07:23:13","slug":"therapies-for-alzheimers-disease","status":"publish","type":"post","link":"https:\/\/www.bocsci.com\/blog\/therapies-for-alzheimers-disease\/","title":{"rendered":"Therapies for Alzheimer’s disease"},"content":{"rendered":"

Alzheimer’s disease<\/a>\u00a0(AD)\u00a0is a progressive, fatal disorder without cure. The mechanism(s) of the disease\u00a0is not entirely understood, impeding development of effective therapy. Current\u00a0treatments provide short-term alleviation of some symptoms, but generally have\u00a0poor efficacy and can be accompanied by moderate to severe side-effects.<\/p>\n

The \u201camyloid cascade hypothesis\u201d\u00a0posits that self-assembly of A\u03b2\u00a0initiates a cascade of events leading to changes in cell membrane conductivity, production of ROS, tau<\/a> hyperphosphorylation, glutamatergic excitotoxicity, deficits in neurotransmitters, including acetylcholine, norepinephrine and serotonin, inflammation, and apoptosis.\u00a0These events cause impairment of neuronal function and neuron death, producing the symptoms of AD. Other hypotheses ascribe etiologic primacy to oxidative stress or related metabolic changes\u00a0resulting from aging\u00a0and argue that A\u03b2-mediated effects occur secondarily to these initial insults.<\/p>\n

Wide acceptance of the amyloid cascade hypothesis has focused therapeutic\u00a0efforts on inhibiting formation, or facilitating elimination, of neurotoxic A\u03b2\u00a0assemblies. Leading approaches are A\u03b2\u00a0immunization, inhibition of A\u03b2\u00a0production, enhancement of A\u03b2\u00a0clearance by specific proteases or general\u00a0proteolytic mechanisms and prevention of A\u03b2\u00a0assembly using a wide variety of chemicals. Other approaches include the use of neuroprotective agents, antioxidants, anti-inflammatory agents, hormone\u00a0replacement therapy, cholinesterase inhibitors and NMDA receptor\u00a0antagonists.<\/p>\n

AChE Inhibitors<\/a> (AChEIs)<\/b><\/strong><\/p>\n

The most commonly used drugs for treatment of AD are cholinesterase inhibitors. During the\u00a0disease, degeneration of cholinergic nuclei localized in the basal forebrain occurs. Impairment of\u00a0the cholinergic system, which projects into\u00a0large areas of the limbic system and the neocortex, is followed by disturbance of\u00a0attentional processes and cognitive decline. In the absence of better therapeutic\u00a0alternatives, treatment of AD-induced cholinergic deficiency was considered an\u00a0attractive and reasonable strategy in the 1980s. By 1993, execution of the\u00a0strategy resulted in FDA approval of the AChEI Tacrine, the first drug specifically approved for the treatment of AD. Tacrine provides modest symptomatic\u00a0relief in mild to moderate cases of AD, but like other AChEIs, it can cause severe side-effects, including nausea, vomiting, diarrhea, constipation,\u00a0headache, dizziness and sleep disturbance. New AChEIs that cause less severe\u00a0side-effects have been developed in the last decade, including Donepezil, Galantamine, Rivastigmine and\u00a0Metrifonate.<\/p>\n

Memantine<\/a><\/b><\/strong><\/p>\n

Memantine is a low-to-moderate affinity, uncompetitive NMDA receptor antagonist that appears to block pathological, but not physiological, activation of\u00a0NMDA receptors. The drug may interfere with glutamatergic excitotoxicity and provide temporary relief to AD patients with moderate-to-severe disease. Memantine has been shown to cause modest improvement in clinical\u00a0symptoms in severe stages of AD and may retard disease progression. Side-effects of memantine are minimal. Strong voltage dependency and rapid blocking\/unblocking kinetics are thought to be the basis for memantine\u2019s clinical tolerability. Clinical studies demonstrate positive effects of memantine in AD both\u00a0as a monotherapy and in combination with AChEI treatment. Memantine\u00a0offers a complementary therapeutic approach to AChEI, which may slow down\u00a0the progress of AD, but like AChEI it is not curative.<\/p>\n

Antioxidants<\/b><\/strong><\/p>\n

Excessive accumulation of ROS contributes to neuronal loss and dysfunction,\u00a0and has been implicated in many studies as one pathological mechanism of AD. Based on these observations, vitamin E, a potent antioxidant and\u00a0neuroprotective agent, is often prescribed as a treatment for AD. A clinical trial\u00a0of vitamin E in patients with moderately advanced AD was conducted by the<\/p>\n

Alzheimer\u2019s Disease Cooperative Study. The results indicated that vitamin\u00a0E may slow functional brain deterioration, confirming results of previous trials. The selective monoamine oxidase inhibitor selegiline also slowed down\u00a0AD progression, but its combination with vitamin E did not improve the outcome relative to each drug alone.<\/p>\n

Immunotherapy<\/b><\/strong><\/p>\n

Based on initial data from in vitro experiments followed by studies in\u00a0rodents, immunization with A\u03b2\u00a0has been a very active area of research. Active and passive immunization strategies have been\u00a0shown to reduce AD-like pathology and restore cognitive deficits in transgenic mice, rabbits, guinea pigs\u00a0and monkeys. These results evoked substantial optimism. Unfortunately, phase IIa\u00a0clinical trials, in which patients with AD were immunized\u00a0with A\u03b2(1-42) in adjuvant QS-21 (preparation AN-1792) were halted because a\u00a0small but significant number of patients developed meningoencephalitis. Post-mortem examination of two treated patients revealed few plaques in\u00a0the neocortex and no dystrophic neurites or reactive astrocytes (as compared\u00a0with unimmunized controls). Reactive microglia associated with areas devoid of\u00a0plaques were not observed. These results suggest that an effective immune\u00a0response was generated in these patients, resulting in clearance of A\u03b2\u00a0plaques.In addition, patients who produced antibodies in response to immunization\u00a0with AN-1792 exhibited slower rates of cognitive decline. Additional studies now\u00a0must be performed to understand the mechanistic basis of the iatrogenic problems and to\u00a0develop safer vaccines for future use.<\/p>\n

Statins<\/b><\/strong><\/p>\n

Statins are molecules that lower plasma levels of LDL and cholesterol, and increase HDL levels. Statins have been in use for many years in the treatment of cardiovascular and other diseases, and are considered safe medications. Recent studies now suggest that statins may be of use for the prevention of AD. It should be noted that these studies involved relatively small numbers of subjects and therefore that the data extant are insufficient to justify the use of statins in the general, non-demented population without hyperlipidemia. Large-scale, placebo-controlled clinical trials will be required to establish the efficacy and safety of statins in prevention and treatment of AD.<\/p>\n

Chelation Therapy<\/b><\/strong><\/p>\n

In vitro<\/i><\/em>\u00a0and\u00a0in vivo<\/i><\/em>\u00a0data have suggested that formation of neurotoxic assemblies of A\u03b2\u00a0is mediated by interaction of A with ions of transition metals such as copper and zinc. This hypothesis led to in vitro studies of the effects of chelators on A\u03b2\u00a0fibril formation and dissociation. These studies showed that chelators could block fibril formation in vitro, dissociate ex vivo amyloid and inhibit A accumulation in vivo. Based on these results, clinical trials were initiated to determine if chelators could be used to treat AD. The chelator chosen for study was clioquinol, a copper and zinc-chelating agent that had been in use for more than 70 years in the treatment of amoebic dysentery. The drug had been in disfavor since the 1970s because many patients developed blindness and paralysis following treatment. Further investigation revealed that these severe adverse effects resulted from deficiency in vitamin B12 and could be prevented by vitamin B12 supplementation. Recently, a phase II clinical trial of clioquinol with vitamin B12 supplementation showed that the cognitive abilities of treated patients stabilized and their plasma A\u03b2\u00a0(1-42) levels were reduced relative to a placebo group. These results suggest that clioquinol, or other chelators, may hold promise as therapeutic agents for AD.<\/p>\n

Hormone Replacement Therapy<\/b><\/strong><\/p>\n

Epidemiologic studies have shown a higher prevalence of AD in women than in men, suggesting a link between gonadal hormone levels and AD. In view of these studies, and of evidence supporting a role for estrogen in brain regions involved in learning and memory and in the protection and regulation of cholinergic neurons, hormone replacement therapy has been studied with respect to its ability to decrease the risk for, or delay the onset of, AD in post-menopausal women. Unfortunately, recent trials have suggested that estrogen treatment has no significant effect on the clinical course of AD in elderly women with the disease. Moreover, the Women\u2019s Health Initiative study of estrogen plus medroxyprogesterone acetate showed an increased risk of dementia among post-menopausal women who showed no cognitive deficits before entering the trial and were in the active-treatment group. Hormone replacement therapy thus does not appear to be a viable approach for the treatment or prevention of AD.<\/p>\n

Anti-inflammatory Drugs<\/a><\/b><\/strong><\/p>\n

Interest in anti-inflammatory drugs has been driven by observations of inflammation in brain regions affected by AD and by studies showing that certain non-steroidal anti-inflammatory drugs (NSAIDs) reduce the likelihood of developing AD. One mechanism by which the NSAID effect is mediated has been suggested by the finding that a subset of NSAIDs specifically reduces A\u03b242 levels, possibly through interaction with the \u03b3-secretase complex and\/or the small G-protein Rho. Long-term use of NSAIDs has been found to reduce AD risk and greater risk reduction was observed among patients with longer NSAID treatment histories. However, other studies have failed to show clear beneficial effects of NSAID treatment. These conflicting data suggest that simple anti-inflammatory treatment of AD patients may be ineffective and that better understanding of the mechanisms by which NSAIDs affect A\u03b2PP processing will be required if the approach is to be successful.<\/p>\n

Reference:<\/h4>\n

Westermark, P., Bellotti, V., Obici, L., Kisilevsky, R., Merlini, G., Sipe, J. D., … & Proteoglycans, E. M. H. S. (2005). Amyloid proteins: the beta sheet conformation and disease.<\/p>\n","protected":false},"excerpt":{"rendered":"

Alzheimer’s disease\u00a0(AD)\u00a0is a progressive, fatal disorder without cure. The mechanism(s) of the disease\u00a0is not entirely understood, impeding development of effective therapy. Current\u00a0treatments provide short-term alleviation of some symptoms, but generally […]<\/p>\n","protected":false},"author":1,"featured_media":691,"comment_status":"open","ping_status":"open","sticky":false,"template":"","format":"standard","meta":[],"categories":[181],"tags":[518,225,40,519,224],"_links":{"self":[{"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/posts\/841"}],"collection":[{"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/posts"}],"about":[{"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/types\/post"}],"author":[{"embeddable":true,"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/users\/1"}],"replies":[{"embeddable":true,"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/comments?post=841"}],"version-history":[{"count":1,"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/posts\/841\/revisions"}],"predecessor-version":[{"id":842,"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/posts\/841\/revisions\/842"}],"wp:featuredmedia":[{"embeddable":true,"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/media\/691"}],"wp:attachment":[{"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/media?parent=841"}],"wp:term":[{"taxonomy":"category","embeddable":true,"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/categories?post=841"},{"taxonomy":"post_tag","embeddable":true,"href":"https:\/\/www.bocsci.com\/blog\/wp-json\/wp\/v2\/tags?post=841"}],"curies":[{"name":"wp","href":"https:\/\/api.w.org\/{rel}","templated":true}]}}