Kur, Ivan M.

Universitat Autònoma de Barcelona. Facultat de Biociències

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MOLECULAR BASIS OF ALZHEIMER’S DISEASEIvan M. KurBachelor’s Thesis – Degree in BiochemistryUniversitat Autònoma de BarcelonaJune 2014INTRODUCTIONAlzheimer’s disease (AD) is a neurodegenerative process in the Central Nervous System (CNS) characterized by a progressive neuronal death in severalzones of the brain, in particular, cortical brain and hippocampus. The loss of immediate memory, a cognitive deterioration and behaviour disorders arealso characteristics of Alzheimer’s disease. The aetiology of the disease is already unknown and there is no existence of a treatment to stop thepathologic process. Several hypothesis have been made and some implications have been found with the intention to explain phenomena and what isgoing on AD.PREVENTION AND TREATMENTThere is no effective treatment against AD. Findings and research for strategies which target the cholinergic system has led to the development ofcholinesterase inhibitors (AChEI) which diminish neuron loss (i.e. Rivastigmine). The synthesis of several antibodies or proteins that inhibitaggregation of β-amyloid or tau protein respectively has been useful to halt the decline in cognitive function and improve it but with someadverse effects (i.e. bapineuzumab, rember).REFERENCES1. Galimberti D. Scarpini E. (2012). Progress inAlzheimer’sdisease. J Neurol 259, 210-211.2. Edgar Dawkins and David H. Small. (2014). Insights into the physiological function of the β-amyloid precursor protein: beyondAlzheimer’sDisease. doi: 10.1111/jnc.12675.3. Chia-Chen Liu, Takahisa Kanekiyo, Huaxi Xu, and Guojun Bu. (2013). Apolipoprotein E and Alzheimer disease: risk, mechanisms,and Therapy. Nat Rev Neurol. 9(2): 106–118. doi:10.1038/nrneurol.2012.263.4. Sung S. Choi, Sang-Rae Lee, Seung U. Kim and Hong J. Lee. (2014). Alzheimer’s Disease and Stem Cell Therapy. Exp Neurobiol.Mar;23(1):45-52.5. Miguel Medina, Jesús Avila. (2014). New perspectives on the role of tau in Alzheimer’s disease. Implications for therapy.Biochemical Pharmacology 88 540-547.CHOLYNERGIC HYPOTHESISThe loss of acetylcholine (ACh) neurons is a hallmark in AD. Ach inthe synaptic cleft is catabolized by cholinesterases, implicated inbehavioural functions including learning and memory.TAU PROTEIN HYPOTHESISTau’s abnormal hyper-phosphorylationin AD results in toxic gain of functionand formation of neurofibrillary tanglesof paired helical filaments (PHF).PSEN IMPLICATIONPresenilins (code by PSEN) function asthe catalytic subunit of γ-secretase.Some mutations in two conservedaspartate (thought to be part of thecatalytic domain) cause loss of function.AMYLOID HYPOTHESISBased on theexcessiveaccumulation ofamyloid-β peptide inaggregate formsoutside neurons bycleavage of APPwhich results in in theproduction oftruncated Aβ peptide..APOE IMPLICATIONMutation of ε4 allele in APOE genecoding for Apo-lipoprotein Estimulates AD causing acceleratedcognitive decline with age andmemory loss. ApoE is important inthe metabolism of Aβ to carry itfrom the brain to systemiccirculation for degrading.PROGRESS IN ALZHEIMER’S THERAPYAlzheimer’s therapies so far have revolved around retarding the progression of the disease rather than restoring the damaged neurons. However,the recent trend is to focus on removing the causes of the disease with stem cell-based therapies. If the causes of AD are understood more deeplyand safer cell therapies are developed, AD could be conquered in the not too distant future.CONCLUSIONSLatest research direction of Alzheimer focuses on early diagnosis(biomarker’s finding), given that the administered medication upon theinitial manifestation of the disease can help to maintain the quasi-normalstate of cognitive functions longer. Studies will show in the coming yearsthe potential effectiveness of these strategies, which are the expectancyfor the treatment of Alzheimer's disease.

Molecular basis of Alzheimer's disease

http://ddd.uab.cat/pub/tfg/2014/123547/TFG_ivanmkur.pdf

Molecular basis of Alzheimer's disease

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