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Alzheimer’s Disease: Current Therapies and Emerging Research Kanan Shah and Vivek Pisharody Introduction he greatest challenge in the development of efective treatments for the neurodegenerative disorder Alzheimer’s Disease (AD) is the lack of scientiic consensus on its cause. Numerous hypotheses and mechanisms have been proposed, but no current hypothesis explains all observed symptoms of this disease. AD is clinically characterized by the rapid loss of cognitive ability and memory. Anatomically, AD begins with the appearance of extracellular deposits of insoluble amyloid-β protein (Aβ), known as senile plaques, and the formation of neuroibrillary tangles (NFTs). Traditionally, two clinically similar forms of AD have been described: Familial Alzheimer’s Diseases (FAD), a hereditary form of AD, and Sporadic Alzheimer’s Disease (SAD), which can develop in individuals with no family history of AD. While numerous hypotheses have been posited, the mechanism by which Alzheimer’s Disease develops is still unknown [1]. It is also uncertain whether the initial causes of FAD and SAD are diferent. Furthermore, although Aβ plaques and NFTs are always found in AD brain, Aβ and NFTs may only represent a inal product of progressive neurodegeneration due to AD, rather than a cause [2]. Despite decades of research, there remains much to be discovered about this mysterious disease. Two Classic Hypotheses Traditionally, two main causal mechanisms for the development and progression of AD have been proposed. First, the Aβ “cascade” hypothesis proposes that excess production of amyloid-β, a small ibrillar peptide, leads to the accumulation of extracellular senile plaques in the spaces around synapses, which in turn lead to neurodegeneration and apoptosis [1]. Aβ is formed by the cleavage of amyloid precursor protein (APP), which is encoded by a gene located on the twenty-irst chromosome. he released amyloid peptide then travels to the extracellular spaces and forms Aβ plaques. Current therapies for AD utilize a variety of mechanisms, but the majority of treatments aim to decrease amyloid production. However, the classical Aβ “cascade” hypothesis has come under scrutiny as Aβ deposits do not correlate with clinical symptoms, and Aβ plaques have been found in the brains of individuals without AD [4]. Unlike insoluble Aβ deposition, soluble Aβ concentration does correlate with cognitive impairment. Recent research indicates that the soluble Aβ oligomers, which are comprised of protoibril Aβ and Aβ-derived difusible ligands (ADDL), are also
toxic [2]. Aβ oligomers are hypothesized to contribute to suppression of long-term potentiation, the strengthening of synapses between cells in memory recall, and may be the major cause of synaptic dysfunction during early stages of AD [1,4]. ADDLs bind to receptors on neurons, thereby changing the structure of synapses and disrupting neural communication [3]. Protoibrils, soluble intermediates found in the process of amyloid ibril formation, may contribute to neuronal death later in the progression of AD [3]. Moreover, evidence has shown that N-APP, a relative of the Aβ protein, may be more signiicant in neural degeneration than the Aβ protein. N-APP, a fragment of APP from its N-terminus, is cleaved from APP by one of the same enzymes that cleaves Aβ. N-APP causes apoptosis by binding to a cell site that induces cell death [3]. he other classical hypothesis centers on the hyperphosphorylation of Tau, a microtubule-associated protein that stabilizes nerve cells’ structures. Tau hyperphosphorylation is thought to cause it to dissociate from microtubules and accumulate in intracellular neuroibrillary tangles (NFTs) [5,6]. When abnormally phosphorylated, Tau reduces its ainity for and dissociates further from microtubules, accumulated in the neuronal perikarya and processed as paired helical ilaments (PHF) [7]. he abnormal NFTs lead to a loss of dendritic microtubules and synapses, membrane degeneration, and ultimately cell death. In addition, hyperphosphorylated Tau also sequesters normal Tau molecules into the aggregates, which in turn have a negative impact on the normal microtubule function. Recent research supports that only the soluble, oligomeric forms of Tau are pathogenic, a result similar to the one found in the Aβ hypothesis[5]. Mutations that increase the risk of early-onset AD and tau hyperphosphorylation are colocalized with genes linked to Aβ plaque production. hese genes encode for APP and for membrane- spanning proteins presenilin-1 (PS-1) and PS-2 that process APP. herefore, it is postulated that either the Tau gene mutation or the accumulation of Aβ plaques can trigger the accumulation of hyperphosphorylated Tau protein [6]. Alternative Pathways and Mechanisms hough the two classical hypotheses described above have dominated AD research for the past quarter century, new research has revealed that a variety of biological mechanisms may be implicated in this disease.
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Street Broad Scientific Glycogen Synthase Kinase 3 Despite its name, the serine/threonine kinase, known as glycogen synthase kinase 3 (GSK 3), has important functions outside of glycogen synthesis, and is known to be crucial to mechanisms as varied as Wnt signaling, apoptosis, cell development and diferentiation, metabolic homeostasis, inlammation, and cell polarity. GSK 3 has been linked to an incredible variety of neurodegenerative diseases [8]. Jope et al. have proposed that inlammation is the causal link between neurodegenerative diseases and GSK 3 as GSK 3 promotes the migration of pro-inlammatory cells and the iniltration of inlammatory molecules into the brain. Triggering Receptor Expressed on Myeloid Cells 2 (TREM2) A rare missense mutation in the gene encoding for TREM2 has been found to interfere with the brain’s ability to prevent the buildup of plaque and is linked to AD. Under normal conditions, the TREM2 gene allows white blood cells in the brain to eliminate the plaque- forming protein Aβ. However, the mutated TREM2 gene reduces white blood cells’ efectiveness in attacking Aβ. People with the mutated gene have ive times as much of a risk of developing AD as they age. In a study of genetic data from around the world, this mutation occurred in 0.5 to 1% of the general population, but in 1 to 2% of patients with AD [11]. his discovery reconsiders the previously ignored inlammation of the brain in AD patients and highlights the role of the immune system in the disease [11]. Translocase of the Outer Mitochondrial Membrane, 40 kD (TOMM40) TOMM40, a recently identiied risk gene for AD on the 19th chromosome, encodes the essential mitochondrial protein import translocase and is adjacent to and in linkage disequilibrium with the apolipoprotein (APOE) gene. Of the three alleles (short, long, and very long), the very long allele is associated with impaired verbal memory recall. his same impairment is seen in APOE ε3/ε4 subjects with a family history of AD [12]. Although APOE ε 4 and TOMM40 are associated with each other, recent research indicates that APOE ε 4 and TOMM40 inluence age-related memory but do so independently of each other. TOMM40 has a signiicant efect only before the age of 60, while APOE ε3/ε4 only has a signiicant efect after the age of 60 [13]. Current herapeutic Approaches As AD has no known cure, current treatment is generally centered on maintaining quality-of-life. Treatments for AD often focus on symptoms; conventional treatments for depression, anxiety, and psychosis are used as they would be in non-AD patients. here are currently two major classes of medication that directly address AD, cholinesterase inhibitors and glutamate inhibitors [14,15].
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REviEw Cholinesterase (ACh) inhibitors Cholinesterase inhibitors, the irst class of AD medication developed, attempt to increase cognitive ability by increasing levels of the neurotransmitter Ach [15]. While the exact mechanism of each drug varies, all drugs in this class work by reducing the efectiveness of acetylcholinesterase (AChE), the enzyme responsible for the breakdown of ACh. Elevated ACh levels temporarily increase the ability of neurons to transfer signals to other neurons, thereby increasing cognition. his class of medication has long been considered a irst line of action against mild to moderate AD. However, cholinesterase inhibitors have severe shortcomings. he efects of cholinesterase inhibitors are short-term, and many patients do not respond to this therapy [16]. Furthermore, these drugs have no efect on the observed anatomy of the disease; Aβ plaques and NFTs remain unchanged. Glutamate Inhibitors he second category of drugs available for AD also attempts to increase neurotransmission, but instead targets glutamate, another neurotransmitter [17]. Keltner and Williams note that sustained glutamate signaling has been linked to cognitive decline and neuronal death through excitotoxicity, a mechanism in which hyperactivity of an enzyme causes cell damage and death. Currently, only one drug in this class, memantine hydrochloride, has been FDA-approved for AD treatment. Memantine HCl has been approved for mild to moderate AD and reduces abnormal, sustained signaling of glutamate while leaving normal glutamate action unafected. However, there is insuicient clinical data to conirm whether memantine hydrochloride will have long-term efects on neurodegeneration. Furthermore, like cholinesterase inhibitors, memantine HCl does not afect NFTs or Aβ plaques [18]. Medicines in Development In addition to these existing classes of medication, Niikura et al. investigated proposed therapeutic options based on the Aβ hypothesis [3]. hese approaches focus on the removal of Aβ plaques. Possible mechanisms of Aβ removal include suppression of the secretases responsible for the production of Aβ from APP, accelerating the rate of natural Aβ degradation by enzymes in the brain, and immunization against Aβ. However, methods to increase the rate of Aβ removal are still in their infancy, and immunization against Aβ in human trials resulted in a signiicant inlammatory response. Niikura et al. reported an alternative method to combat AD-related neurodegeneration. Using Humanin, a novel neuroprotective compound, Niikura demonstrated that neurons can be successfully protected from the damaging efects of Aβ, and hypothesized that suicient neuroprotection, combined with some level of Aβ removal, can avert neuronal death entirely.
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REviEw Computational Models and Advancement in AD Research Recently, developments in computational neuroscience have provided a way to integrate the many factors inluencing the progression of AD, including the relative contribution of cell death, slowing of conduction velocities, and normal aging processes, into a complex system that mediates the interaction between the proposed mechanisms [19]. In 1994, Alvarez and Squire proposed a model of the role of key neural regions involved in AD, the hippocampus and neocortex [20]. hey assumed learning between the two occurs quickly, whereas forgetting occurs at a moderate rate. In addition, intra-neocortical learning and forgetting occur slowly. his model showed the hippocampus slowly teaching the neocortex, and when lesioned, the model simulates the response of AD brain. he advantage of this model is that it shows associations learned in early cycles, but a disadvantage is that it does not perform well on memories learned in later cycles. he model can also be used to determine how much information is lost between neocortical regions and between the neocortex and hippocampus [21]. More recently, Glaw and Skalak have developed a model to test the hypothesis that GSK-3 provides a possible link between Aβ buildup and NFT development [21]. his model found that GSK-3 had a large efect on NFT formation, but very little on plaque formation, with no link found between A plaques and NFTs [22]. Computational models continue to be improved and reused to further analyze data. For example, a 1995 model by Ruppin and Reggia showed how lesions in a neural network lead memory loss, and adding a local compensation factor causes a pattern of functional damage similar to that found in AD. Rowan enhanced this model with techniques more representative of current knowledge of the disease. In Rowan’s model, the high density of local connections leads to synaptic redundancy and increased protection against damage [22]. his model showed that by silencing the output of selected neurons to simulate the efects of axonal binding blocked by NFTs, initial retrieval of remote memories is more reliable than retrieval of recent memories at early stages of damage. If the brain continues to make use of this efect and uses the more readily available remote memories, the recently-stored memories continue to become less reliable and recall performance for recent patterns decreases. his result is similar to that seen in clinical studies [22].
Conclusion he true cause of Alzheimer’s Disease continues to be an enigma, but recent research has elucidated many possible avenues for the development of new therapies. he classical amyloid-β and Tau hypotheses have been insuficient to explain the complexities of this disease; however, newer mechanisms, like GSK3, and genetic targets,
like TOMM40, provide new insights. Furthermore, new computational models may provide the key to developing efective treatments.
References [1] Hooper C, Killick R, Lovestone S. he GSK3 hypothesis of Alzheimer’s disease. Journal of neurochemistry. 2008 Mar;104(6):1433–9. [2] Hernández F, Avila J. he role of glycogen synthase kinase 3 in the early stages of Alzheimers’ disease. FEBS letters. 2008 Nov 26;582(28):3848–54. [3] Niikura T, Tajima H, Kita Y. Neuronal cell death in Alzheimer’s disease and a neuroprotective factor, humanin. Current neuropharmacology. 2006;139–47. [4] Avila J, Medina M. he Role of Glycogen Synthase Kinase-3 ( GSK-3 ) in Alzheimer ’ s Disease. In: De La Monte S, editor. Alzheimer’s Disease Pathogenesis-Core Concepts, Shifting Paradigms and herapeutic Targets. INTECH; 2011. p. 197–210. [5] Maccioni RB, Farías G, Morales I, Navarrete L. he revitalized tau hypothesis on Alzheimer’s disease. Archives of medical research. 2010 Apr;41(3):226–31. [6] Brich J, Shie F-S, Howell BW, et al. Genetic modulation of tau phosphorylation in the mouse. he Journal of neuroscience : the oicial journal of the Society for Neuroscience. 2003 Jan 1;23(1):187–92. [7] Takashima A. GSK-3 is essential in the pathogenesis of Alzheimer’s disease. Journal of Alzheimer’s Disease. 2006;9:309–17. [8] Jope RS, Yuskaitis CJ, Beurel E. Glycogen synthase kinase-3 (GSK3): inlammation, diseases, and therapeutics. Neurochemical research. 2007;32(4-5):577–95. [9] Hur E-M, Zhou F-Q. GSK3 signalling in neural development. Nature reviews Neuroscience. Nature Publishing Group; 2010 Aug;11(8):539–51. [10] Zafra D, Corominola H, Domı J, Gomis R, Guinovart JJ. Sodium Tungstate Decreases the Phosphorylation of Tau hrough GSK3 Inactivation. Journal of Neuroscience Research. 2006;273(October 2005):264–73. [11] Jonsson T, Stefansson H, Ph.D. SS, et al. Variant of TREM2 Associated with the Risk of Alzheimer’s Disease. New England Journal of Medicine. 2012 Nov 14;107–16. [12] De Strooper B. Loss-of-function presenilin mutations in Alzheimer disease. Talking Point on the role of presenilin mutations in Alzheimer disease. EMBO reports. 2007 Feb;8(2):141–6. [13] Caselli RJ, Dueck AC, Huentelman MJ, et al. Longitudinal modeling of cognitive aging and the TOMM40 efect. Alzheimer’s & dementia : the journal of the Alzheimer’s Association. Elsevier Ltd; 2012 Nov;8(6):490–5. [14] Birks J. Cholinesterase inhibitors for Alzheimer’s disease (Review). 2012. [15] hacker PD. Surprising discovery with Alzheimer’s Medication. Drug Discovery Today. 2003;8(9):379–80. Volume 2 | 2012-2013 | 61
Street Broad Scientific [16] Pepeu G, Giovannini MG. Cholinesterase inhibitors and memory. Chemico-biological interactions. Elsevier Ireland Ltd; 2010 Sep 6;187(1-3):403–8. [17] Keltner NL, Williams B. Biological Perspectives Memantine : A New Approach to Alzheimer ’ s Disease. Perspectives in Psychiatric Care. 2003;10(3):4–5. [18] Mark LP, Prost RW, Ulmer JL, et al. Pictorial review of glutamate excitotoxicity: fundamental concepts for neuroimaging. AJNR American journal of neuroradiology. 2001;22(10):1813–24. [19] Jedynak BM, Lang A, Liu B, et al. A computational neurodegenerative disease progression score: Method and results with the Alzheimer’s disease neuroimaging initiative cohort. NeuroImage. Elsevier Inc.; 2012 Nov 15;63(3):1478–86. [20] Alvarez P, Squire LR. Memory consolidation and the medial temporal lobe: a simple network model. Proceedings of the National Academy of Sciences of the United States of America. 1994 Jul 19;91(15):7041–5. [21] Crystal H, Finkel L. Computational approaches to neurological disease. World Scientiic. 1996. [22] Rowan M. Efects of Compensation, Connectivity and Tau in a Computational Model of Alzheimer’s Disease. International Joint Conference on Neural Networks. 2011 Jun 30;1–8.
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