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New Insights on Alzheimer's Disease G Model JMAU-19; No. of Pages 10 ARTICLE IN PRESS Journal of Microscopy and Ultrastructure xxx (2014) xxx–xxx Contents lists available at ScienceDirect Journal of Microscopy and Ultrastructure jour nal homepage: www.elsevier.com/locate/jmau Review New insights on Alzheimer’s disease ∗ Randa Abdel Kader Mahmoud El-Desouki Department of Biochemistry and Molecular Medicine, Faculty of Medicine, Taibah University, Almadinah Almunawwarah, Saudi Arabia a r a t b i c s t l e i n f o r a c t Article history: Alzheimer’s disease (AD), the most common age-associated dementing disorder, is clin- Received 6 November 2013 copathologically manifested by progressive cognitive dysfunction concomitant with the Accepted 25 January 2014 accumulation of senile plaques (SP). SP is consisting of amyloid-␤ (A␤) peptides and neu- rofibrillary tangles (NFTs) of hyper-phosphorylated tau (p-tau) protein aggregates in the brain of affected individuals. Lipid rafts promote interaction of the amyloid precursor pro- Keywords: tein (APP) with the ␤-secretase enzyme responsible for generation of the A␤ peptides. Alzheimer’s disease (AD) Fibrillar A␤ oligomers, which have been shown to correlate with the onset and severity of Lipid rafts C Amyloid precursor protein (APP) AD, bind preferentially to cells and neurons expressing cellular prion protein (PrP ). The C ␤ Amyloid ␤ (A␤) peptide binding of A oligomers to cell surface PrP , as well as their downstream activation of ␣ ␤ ␥ -, -, -Secretases Fyn kinase, was dependent on the integrity of cholesterol-rich lipid rafts. Rafts also regu- C Cellular prion protein (PrP ) late cholinergic signaling as well as acetylcholinesterase and A␤ interaction. Such major lipid raft components as cholesterol and ganglioside (GM1) have been directly implicated in pathogenesis of the disease. Perturbation of lipid raft integrity can also affect various signaling pathways leading to cellular death and AD. In this review, I will discuss the more recent findings on the biopathological mechanisms, candidate bio-markers, and therapeutic interventions of the elusive AD. © 2014 Saudi Society of Microscopes. Production and hosting by Elsevier Ltd. All rights reserved. Contents 1. Introduction . 00 2. Lipid rafts . 00 3. Lipid raft components and their changes in AD . 00 3.1. Raft localization of APP and secretases . 00 3.2. Generation of A␤42 . 00 3.3. Cellular mechanisms of A␤ oligomer-mediated neurotoxicity . 00 C 3.3.1. Cellular prion protein (PrP ) signaling in AD . 00 3.4. APP sorting, transport, trafficking and processing . 00 4. Genetic studies/bioinformatics analysis . 00 4.1. Familial Alzheimer’s disease (FAD) . 00 ∗ Tel.: +966 543676660. E-mail address: [email protected] Peer review under responsibility of Saudi Society of Microscopes. 2213-879X © 2014 Saudi Society of Microscopes. Production and hosting by Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.jmau.2014.01.002 Please cite this article in press as: El-Desouki RAKM. New insights on Alzheimer’s disease. J Microsc Ultrastruct (2014), http://dx.doi.org/10.1016/j.jmau.2014.01.002 G Model JMAU-19; No. of Pages 10 ARTICLE IN PRESS 2 R.A.K.M. El-Desouki / Journal of Microscopy and Ultrastructure xxx (2014) xxx–xxx 5. Lipids and Alzheimer’s disease connection . 00 5.1. Phospholipids . 00 5.2. Gangliosides (GM) . 00 5.3. Cholesterol . 00 5.4. Statins . 00 6. Factors influencing the initiation and progression of AD . 00 6.1. Lipid raft redox signaling . 00 6.2. Oxidative stress and neuronal death . 00 6.3. Inflammation and neuronal death. 00 6.4. Cholinergic system and AD . 00 6.5. Exosomes and microRNAs . 00 6.6. Dietary and environmental factors . 00 7. AD-type 2 diabetes (T2DM) co-morbidity . 00 8. AD diagnosis . 00 8.1. Lipids as biomarkers for AD diagnosis . 00 9. Conclusion . 00 Conflict of interest . 00 References . 00 1. Introduction Although there are strong genetic links, including APP, PS-1, and PS-2 mutations [12], as well as the apolipopro- tein ␧4 allele [13], sporadic AD is the dominant form. From Alzheimer’s disease (AD) is a common, progressive and this point of view pre-dominance of AD research based on devastating neuro-degeneration of human brain structure the mechanisms of early onset disease versus the broader and function, from which over 37 million people are suffer- spectrum of the factors leading to the sporadic form might ing worldwide [1] with an estimated cost of $600 billion in be one of the reasons for the failure of the majority of ther- 2010 [2]. Globally, 5 million new cases of AD are diagnosed apeutic trials and lack of any preventive measures 20 years annually, with one new AD case being reported every 7 s [3]. since the amyloid hypothesis has been proposed [14]. The risk of developing AD correlates strongly with aging, In this review, I will elaborate on the current status of resulting in a deterioration of mood, behavior, functional research addressing the biopathological mechanisms, can- ability, cognition, and memory [4], therefore, AD is becom- didate bio-markers, and therapeutic interventions of the ing an increasing socio-economic crisis as life expectancy elusive AD. increases. Taking care of AD patients places a tremendous socioeconomic burden not only on unpaid caregivers but on our health care system as a whole [5]. In spite of this, 2. Lipid rafts there is no current therapy that can halt or reverse AD [6]. The notion of lipid rafts, while not new, has never The disease is associated with brain pathology involv- been far from controversy, their existence frequently ing accumulation of extracellular.
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