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[supporting online material clathrin paper.docx](https://mdr.nims.go.jp/filesets/94eac457-4274-401a-b120-7e45a69cb954/download)

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Komal Saxena, Pushpendra Singh, Parama Dey, Marielle Aulikki Wälti, Pathik Sahoo, Subrata Ghosh, Soami Daya Krishnanda, Roland Riek, [Anirban Bandyopadhyay](https://orcid.org/0000-0002-8823-4914)

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[Amyloid-β Can Form Fractal Antenna-Like Networks Responsive to Electromagnetic Beating and Wireless Signaling](https://mdr.nims.go.jp/datasets/2326f246-2ce4-4634-a18c-da3c7a644f2c)

## Fulltext

Supporting Info. 1. Tau usually acts as a binder and stabilizer for microtubules, which are like railroad-track that direct nutrients and other molecules, and tau work on it to keep the rails in perfect position. It usually works within a neuron’s axon, or output stalk. Microtubules continuously develop and obliterate in active neurons. Tau’s supports these acute changes, and its microtubule-binding properties continuously refine by adding or eliminating small molecules called phosphor group. Enzymes play an important role to keep the process is reversible. Kinases enzymes weaken the tau’s hold by adding phosphor groups to any of dozen sites on the tau protein, whereas the role of other enzymes called phosphatases is to de-phosphorylating of tau and increase its binding property with microtubule. The reversible process in AD is disturbed and only tau phosphorylation process is at an extreme. In this way tau proteins attach with phosphor groups at many sites to become hyperphosphorylated and separate from the microtubule. Or in other words, rail tracks like microtubule do not have anything to hold and fall apart. These hyperphosphorylated tau proteins begin to pair with other tau protein and get tangled. Consequently, insoluble threads like fibers or fibrils build up and therefore, it is known as neurofibrillary tangles. This process disturbs the whole transport system and affects the communication process between the neurons. Matsuyama, S. S., & L. F. Jarvik, “Hypothesis: microtubules, a key to Alzheimer disease,” Proceedings of the National Academy of Sciences86(20), pp-8152-8156, (1989).Desai A. &Mitchison T.J. Microtubule polymerization dynamics. Annu. Rev. Cell Dev. Biol. 13, 83-117, (1997).Johnson, Gail VW, and Judith A. Hartigan, "Tau protein in normal and Alzheimer's disease brain: an update," Journal of Alzheimer's disease1, no. 4-5, 329-351, (1999).CarloBallatorre, Virginia M.-Y. Lee, and John Q. Trojanowski. Tau-mediated neurodegeneration in Alzheimer’s disease and related disorders. Nature Reviews Neuroscience 8 (9), 663-72, (2007). Lim, Sungsu, Md Mamunul Haque, Dohee Kim, Dong Jin Kim, and Yun Kyung Kim, "Cell-based models to investigate Tau aggregation," Computational and structural biotechnology journal12, no. 20-21, pp 7-13, (2014).Kadavath, H., R. V. Hofele, J. Biernat, S. Kumar, K. Tepper, H. Urlaub, E. Mandelkow, and M. Zweckstetter, “Tau stabilizes microtubules by binding at the interface between tubulin heterodimers,” Proceedings of the National Academy of Sciences, p.201504081, (2015).Stepanek, Ludek, and Gaia Pigino. "Microtubule doublets are double-track railways for intraflagellar transport trains." Science 352, no. 6286 (2016): 721-724.Arioka, Manabu, Masamitsu Tsukamoto et al. τ Protein kinase II is involved in the regulation of the normal phosphorylation state of τ protein. Journal of neurochemistry 60 (2), 461-468, (1993).Iqbal, Khalid, Fei Liu, and Cheng-Xin Gong. Tau and neurodegenerative disease: the story so far, Nature Reviews Neurology 12, no. 1, 15, (2016).Another prime suspect of AD is A plaques. Due to the aggregates of protein in insoluble form and characteristics of resistant degradation, it is names as amyloid. These protein fragments are formed normally in the body by breaking down membrane bound large protein, called amyloid precursor protein (APP), and they are gathered outside the cell between the neuron in the brain. It is removed immediately in healthy brain, while the ability to remove it in AD is slow down and causes the accumulation of A. Furthermore, cell-to-cell communication is affected between the neurons and blocking the signal at the synapse, leading to the neuron cell death. 39-43 amino acid residues of are responsible for accumulation of A. Like A peptide in Alzheimer’s diseases, particular proteins peptides are responsible for other neurodegenerative disease; alpha synuclein protein peptide for Parkinson’s diseases, Huntington protein peptide for Huntington’s diseases, amylin peptide for Type II Diabetes, human prion protein peptide for Creutzfeldt-Jakob Disease (CJD). Goedert, Michel. Alpha-synuclein and neurodegenerative diseases," Nature Reviews Neuroscience  2, no. 7, p. 492, (2001).Kim J, Onstead L, Randle S, et al. Abeta40 inhibits amyloid deposition in vivo. J Neurosci27, 627 – 633, (2007).Kametani, Fuyuki, and Masato Hasegawa. "Reconsideration of Amyloid Hypothesis and Tau Hypothesis in Alzheimer's Disease." Frontiers in neuroscience 12 :25,(2018).Scheuner D, Eckman C, Jensen M., et al.. Secreted amyloid b-protein similar to that in the senile plaques of Alzheimer’s disease is increased in vivo by the presenilin 1 and 2 and APP mutations linked to familial Alzheimer’s disease. Nature Med 2: 864 – 870, (1996). Bates, Gillian P., Ray Dorsey, James F. Gusella, Michael R. Hayden, Chris Kay, Blair R. Leavitt et al., "Huntington disease," Nature reviews Disease primers1, 15005, 2015.Middleton, Chris T., Peter Marek, Ping Cao, Chi-cheng Chiu et al. Two-dimensional infrared spectroscopy reveals the complex behaviour of an amyloid fibril inhibitor. Nature chemistry 4, no. 5, 355, (2012).Alois Alzheimer was first scientist to note these unusual neuropathology characteristics in the brain of his patient’s (Auguste D.), who was suffering from the progressive dementia. In 1911, again he published a paper on the case of another patient (Josef F.), who had AD before his death, but he had not found any neurofibrillary tangles at that time. Still it remains a topic of discussion that having plaque only belongs to the same class as with tangles and plaque together. Scientists are continuing their hypothesis on the basis of amyloid and neurofibrillary tau tangles.Alzheimer A. ÜbereineeigenartigeErkrankung der Hirnrinde. Allgemeine ZeitschriftfürPsychiatrie und Psychisch-GerichtlicheMedizin 64, 146–48, (1907). Alzheimer A. ÜbereigenartigeKrankheitsfälle des späteren Alters. Z Ges Neurol Psychiatr 4, 356-385, (1911). According to the tau hypothesis, microtubule associated tau proteins are considered to be a prime factor of AD. Twisted fibrils of tau protein is accumulated inside the brain in hyperphosporelated state and appeared as paired helical filaments (PHF). In the 19th century, after the case of Auguste D. and Josef F., tau protein or PHF has focused the attention of researchers, who are working on AD. In 1974, neurofibrillary tangles and ~50 kDaPHF were separated from the brain of AD. Scientist also indentified that ~50 kDa PHF is essential for Microtubule assembly and hence it was named as microtubule associated protein. Bulk isolation, protein composition and solubility of Alzheimer PHF were also studied by Iqbal et al.  In 1985, it was reported that PHF antigen(s) level in AD is significantly higher than other neurological patient. A year later, a group of researchers found that microtubule associated tau protein as a key component of Alzheimer PHF. Many researchers found the PHF of tau inside the neuron in AD. If these PHF are formed in cell body of neuron then it is known as neurofibrillary tangles and if these are formed in dendrites then it is known as threads. Any impaired interaction of tau protein with microtubule or any type of deformation of tau protein is lead towards the tau pathology. Based on the tau pathology, braak and braak discussed the six stages of AD. According to him, neurofibrillary changes exist in a single layer of transentorhinal region in stage I and II. Then, it gets extended into the limbic region in III and IV stage. Severe changes are found in stage V and VI and spread to the isocortical region. It has been reported that tau pathology occurs before the amyloid accumulation. Throughout the 2000s, scientists found more and more evidence in the favor of tau pathology. Recently, it is reported that spatial pattern of tau pathology is also thoroughly connected to neurodegeneration and amyloid hypothesis. These theories are in favor of tau pathology. Diseases associated with tau pathology are called as tauopathies. Iqbal, K. et al. Protein changes in senile dementia. Brain Res. 77, 337–343 (1974).Weingarten, M. D., Lockwood, A. H., Hwo, S. Y. & Kirschner, M. W. A protein factor essential for microtubule assembly. Proc. Natl Acad. Sci. USA 72, 1858–1862 (1975).Grundke-Iqbal, I., Johnson, A. B., Wisniewski, H. M., Terry, R. D. & Iqbal, K. Evidence that Alzheimer neurofibrillary tangles originate from neurotubules. Lancet 1, 578–580 (1979).Grundke-Iqbal, I., Johnson, A. B., Terry, R. D., Wisniewski, H. M. & Iqbal, K. Alzheimer neurofibrillary tangles: antiserum and immunohistological staining. Ann. Neurol. 6, 532–537 (1979).Iqbal, K., Zaidi, T., Thompson, C. H., Merz, P. A. & Wisniewski, H. M. Alzheimer paired helical filaments: bulk isolation, solubility, and protein composition. Acta Neuropathol. 62, 167–177 (1984).Mehta, P. D., Thal, L., Wisniewski, H. M., Grundke-Iqbal, I. & Iqbal, K. Paired helical filament antigen in CSF. Lancet 2, 35 (1985).Grundke-Iqbal, I. et al. Microtubule-associated protein tau. A component of Alzheimer paired helical filaments. J. Biol. Chem. 261, 6084–6089 (1986).Grundke-Iqbal, I. et al. Abnormal phosphorylation of the microtubule-associated protein τ (tau) in Alzheimer cytoskeletal pathology. Proc. Natl Acad. Sci. USA 83, 4913–4917 (1986).Delacourte, A. &Defossez, A. Alzheimer’s disease: Tau proteins, the promoting factors of microtubule assembly, are major components of paired helical filaments. J. Neurol. Sci. 76, 173–186 (1986).Braak, H., Braak, E., Grundke-Iqbal, I. & Iqbal, K. Occurrence of neuropil threads in the senile human brain and in Alzheimer’s disease: a third location of paired helical filaments outside of neurofibrillary tangles and neuritic plaques. Neurosci. Lett. 65, 351–355 (1986).Grundke-Iqbal, I. et al. Microtubule-associated polypeptides tau are altered in Alzheimer paired helical filaments. Brain Res. 464, 43–52 (1988)Wischik, C. M. et al. Structural characterization of the core of the paired helical filament of Alzheimer disease. Proc. Natl Acad. Sci. USA 85, 4884–4888 (1988)Bancher, C. et al. Accumulation of abnormally phosphorylated tau precedes the formation of neurofibrillary tangles in Alzheimer’s disease. Brain Res. 477, 90–99 (1989). Braak, H. &Braak, E. Neuropathological stageing of Alzheimer-related changes. Acta Neuropathol. 82, 239–259 (1991).Gong, C. X., Liu, F., Grundke-Iqbal, I. & Iqbal, K. Impaired brain glucose metabolism leads to Alzheimer neurofibrillary degeneration through a decrease in tau O‑GlcNAcylation. J. Alzheimers Dis. 9, 1–12 (2006).Liu, F. et al. Reduced O‑GlcNAcylation links lower brain glucose metabolism and tau pathology in Alzheimer’s disease. Brain 132, 1820–1832 (2009).Frost, Bess et al. . "Conformational diversity of wild-type Tau fibrils specified by templated conformation change." Journal of Biological Chemistry 284, no. 6, 3546-3551 (2009).Iqbal, K. et al. Tau pathology in Alzheimer disease and other tauopathies. Biochim. Biophys. Acta 1739, 198–210 (2005).Ming Jin et al. Soluble amyloid β-protein dimers isolated from Alzheimer cortex directly induce Tau hyperphosphorylation and neuritic degeneration. PNAS 108 (14), 5819-24, (2011).Roberson, E. D. et al. Amyloid‑β/Fyn-induced synaptic, network, and cognitive impairments depend on tau levels in multiple mouse models of Alzheimer’s disease. J. Neurosci. 31, 700–711 (2011).De Calignon, A. et al. Propagation of tau pathology in a model of early Alzheimer’s disease. Neuron 73, 685–697 (2012).Maruyama, M. et al. Imaging of tau pathology in a tauopathy mouse model and in Alzheimer patients compared to normal controls. Neuron 79, 1094–1108 (2013).Zhang, Z. et al. Cleavage of tau by asparagine endopeptidase mediates the neurofibrillary pathology in Alzheimer’s disease. Nat. Med. 20, 1254–1262 (2014).Spillantini, M. G. et al. Familial multiple system tauopathy with presenile dementia: a disease with abundant neuronal and glial tau filaments. Proc. Natl Acad. Sci. USA 94, 4113–4118 (1997).Bejanin, Alexandre, Daniel R. Schonhaut et al. Tau pathology and neurodegeneration contribute to cognitive impairment in Alzheimer’s disease." Brain 140, no. 12, 3286-3300, (2017).Kametani, Fuyuki, and Masato Hasegawa. "Reconsideration of Amyloid Hypothesis and Tau Hypothesis in Alzheimer's Disease." Frontiers in neuroscience 12 :25,(2018).On the other hand, studies during the last 35 years have also enlightened the significant role of A in AD, which caused the generation of amyloid hypothesis. According to the amyloid hypothesis, aggregations of amyloid of different protein composition of peptide in various organs are to be the cause of neurodegenerative disease. Having this idea forward by Glenner et al., they first sequenced a sticky peptide having the cerebrovascular amyloid protein characteristics in the isolated meningeal vessels and individual with Down syndrome in AD brain. Since the beginning of 1980, researchers had started to work on all aspects of A to help patients, who are suffering from this disastrous disease. Fibril structure of A in different clinical condition and environment were also studied. Compared to any other molecules, highly polymorphic character of A fibrils was also studied based on different aggregation and growth condition in AD using nuclear magnetic resonance, electron microscopy, and etc. These researches in the favour of A hypothesis made it dominant in the field of AD pathogenesis.  Glenner, George G., and Caine W. Wong. Alzheimer's disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem. Biophys. Res. Commun 120, 885-890, (1984). Glenner GG, Wong CW. Alzheimer’s disease and Down’s syndrome: sharing of a uniquecerebrovascular amyloid fibril protein. Biochem. Biophys. Res. Commun122, 1131–1135, (1984). Lu., un-Xia, Wei Qiang, et al. Molecular Structure of b-Amyloid Fibrils in Alzheimer’s Disease Brain Tissue. Cell 154, 1257–1268, (2013). Lansbury, P.T., Jr., Costa, P.R., et al. Structural model for the b-amyloid fibril based on interstrand alignment of an antiparallel-sheet comprising a C-terminal peptide. Nat. Struct. Biol. 2, 990–998, (1995).  Benzinger, T.L.S., Gregory, D.M et al. Propagating structure of Alzheimer’s -amyloid (10-35) is parallel b-sheet with residues in exact register. Proc. Natl. Acad. Sci. USA 95, 13407–13412, (1998). Bertini, I., Gonnelli, L., Luchinat, C., Mao, J.F., and Nesi, A. A new structural model of A40 fibrils. J. Am. Chem. Soc. 133, 16013–16022, (2011). Goldsbury, C., Frey, P., Olivieri, V., Aebi, U., and Mu¨ ller, S.A. Multiple assembly pathways underlie amyloid- fibril polymorphisms. J. Mol. Biol. 352, 282–298, (2005). Meinhardt, J., Sachse, C., Hortschansky, P., Grigorieff, N., and Fa¨ ndrich, M. A1-40 fibril polymorphism implies diverse interaction patterns in amyloid fibrils. J. Mol. Biol. 386, 869–877, (2009). Beyreuther K, Masters CL. Amyloid precursor protein (APP) and beta A4 amyloid in the etiology of Alzheimer’s disease: precursor-product relationships in the derangement of neuronal function. Brain Pathol1, 241 – 251, (1991). Selkoe DJ. The molecular pathology of Alzheimer’s disease. Neuron 6, 487 – 498, (1991). Hardy J, Allsop D. Amyloid deposition as the central event in the aetiology of Alzheimer’s disease. Trends in Pharmac 12, 383 – 388, (1991).Hardy JA, Higgins G. Alzheimer’s disease: the amyloid cascade hypothesis. Science 256, 184 – 185, (1992). Hardy J, Selkoe D. J.  The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 297, 353 – 356, (2002). Karran E, Hardy J. A critique of the drug discovery and phase 3 clinical programs targeting the amyloid hypothesis for Alzheimer disease. Ann Neurol76, 185 – 205, (2014). Selkoe, D. J., and J. Hardy. The amyloid hypothesis of Alzheimer’s disease at 25 years.  EMBO mol. Med 8, 595-608, (2016). Although several salutary approach have been explored based on these hypothesis, they either remove the soluble A or reduce the number of A plaques. Until now, there is no complete cure for this devastating disease. Keeping these disappointments results and treatments in mind, there is a need to lead a led mixture of careful thinking. There are many theories in the favor of this. If we talk about the discovery of Alois Alzheimer, he had noted A and NFT both in his patient (Auguste D.) but, for second time, he did not find NFT in the brain of another patient Josef F. Later, Möller and Graeber came up with the conclusion after investigating both cases that these are belong to same disease at different progressive stages. Earlier, in 1985 Masters CL et al. stated that NFTs in AD have the same protein that is in the case of amyloid plaque and blood vessels. It was also reported that accumulations of A deposits come into sight very early and widespread, due to which cellular and molecular alteration such as NFT, microgliosis etc. are formed, whereas tau mutation is not able to accumulate A. In other words, aggregation of A can guide to the progressive deposition of NFT of tau and vise-versa cannot possible. It was also reported that an imbalance between A production and A clearance, causes the formation of NFT.  Doody, R.S., R.G. Thomas, et al. Phase 3 trials of solanezumab for mild-to-moderate Alzheimer's disease. New England Journal of Medicine370(4), 311-321, (2014).Kumar, D., V. Kumar, S. H. Choi, K.J. Washicosky, et al., Amyloid-β peptide protects against microbial infection in mouse and worm models of Alzheimer’s disease. Science translational medicine8 (340), 340ra72, (2016). Sevigny, J., P. Chiao, T. Bussière, P. H. Weinreb, L. Williams, M. Maier, et al. The antibody aducanumab reduces Aβ plaques in Alzheimer’s disease. Nature537(7618), 50-56, (2016). Makin, S., The amyloid hypothesis on trial. Nature559, S4-S7, 2018. Masters CL, Multhaup G, Simms G, Pottgiesser J, Martins RN, Beyreuther K. Neuronal origin of acerebral amyloid: neurofibrillary tangles of Alzheimer’s disease contain the same protein as theamyloid of plaque cores and blood vessels. EMBO J 4, 2757–2763, (1985).  Möller HJ, Graeber MB. The case described by Alois Alzheimer 1911. Eur Arch Psychiatrry Clin Neurosci. 1998; 248:111-127. Lemere CA, Blustzjan JK, et al. Sequence of deposition of heterogeneous amyloid b-peptides and Apo E in Down syndrome: implications for initial events in amyloid plaque formation. Neurobiol Dis 3, 16 – 32, (1996). Lemere CA, Lopera F, Kosik KS, et al. The E280A presenilin 1 Alzheimer mutation produces increased Ab42 deposition and severe cerebellar pathology. Nature Med 2, 1146 – 1150, (1996). Small SA, Duff K, Linking Abeta and tau in late-onset Alzheimer’s disease: a dual pathway hypothesis. Neuron 60, 534 – 542, (2008).Shankar GM, Li S, Mehta TH., et al. Amyloid-beta protein dimers isolated directly from Alzheimer’s brains impair synaptic plasticity and memory. Nat Med 14: 837 – 842, (2008).  Bateman RJ, Xiong C, Benzinger TL, Fagan AM, Goate A, Fox NC, Marcus DS, Cairns NJ, Xie X, Blazey TM et al (2012) Clinical and biomarker changes in dominantly inherited Alzheimer’s disease. N Engl J Med 367: 795 – 804. Hardy J, Selkoe D. J.  The amyloid hypothesis of Alzheimer’s disease: progress and problems on the road to therapeutics. Science 297, 353 – 356, (2002).Selkoe, D. J., and J. Hardy. The amyloid hypothesis of Alzheimer’s disease at25 years.  EMBO mol. Med 8, 595-608, (2016). The aggregation of extracellular beta amyloid plaques and intracellular neurofibrillary beta tangles come into the category of molecular imbalance. However, there are also many genetic and cellular based studies that can explain the cascading effects of AD through their systematic evaluation. First genetic study also supports the amyloid hypothesis, assuming A as the dominating factor in AD. The study has also revealed the correlation of gene APP with AD. The amyloidogenicprocess in the endosomes caused by  and  secretase, and the assembly of A depends on the endocytosis of APP from the membrane to endosomes. APP processing is also regulated by phosphatidylinositol-binding clathrin assembly (PICAM), which is identified as one of the AD associated genes. PICAM encodes Clathrin Assembly Lymphoid Myeloid leukemia (CALM) protein and plays an important role in clathrin-mediated endocytosis. The main function of this protein is to recruit clathrin and adapter proteins for the plasma membrane and to identify the targeted protein with AP2. Triskelions structure of clathrin causes the deformation in plasma membrane around the target protein. In this way, it is helpful in providing appropriate information about the targeted protein to clathrin coated pits in the initial step of clathrin-mediated endocytosis. The Researchers claim that this process is in the synaptic zone of neurons. Variation in PICALM protein is correlated with late-onset AD risk.Baig et al. examined the presence of picalm protein in controlled brain and AD brain and found their dominating occurrence in endothelial cells. They also suggested that transport of A across the vessel walls in the bloodstream could be a major pathway to remove A from the brain. Zhao et al. reported the higher number of PICALM level in the endothelial cells of AD brain, and explained the process of clearing the A  by internalizing them into endothelial cells and then being accompanied with bloodstream. The person suffering from late onset AD has less PICALM level compared to the normal person. Along with the clearance of A from the brain, PICALM also helps in mitigating the toxicity of A in the neuron, in the process of APP internalization and also modulating A production. Kanatsu et al.  reported the opposite behaviour of PICALM in neurons based on mouse model. They involved wild type mice and transgenic mice with low APP expression in their research and found that clearance mechanism of A becomes saturated after injecting the excessive amount of A, whereas less PICALM shows the less aggregation of A. According to the study PICALM promotes the A formation in neurons. These two types of discrepancies raise questions that whether more or less PICALM is good or not. But because of having the most accessible part of endothelial cell, scientists are searching for drugs that can be helpful to clear the A from the brain.  It was also discussed that targeting APP adaptors protein interaction for AD drug development studies can be helpful. In 2015, Poulsen et al. depicted that loss in the Clathrin heavy chain and AP-2 binding to mutate APP is responsible in APP endocytosis resulting the intracellular accumulation. To remove the intracellular tau aggregation, clathrin dependent receptor endocytosis plays an important role for tau antibody uptake. Clathrin mediated endocytosis is also essential for the recycling of synaptic vesicles after releasing each. Many studies have suggested that as a result of increasing the synaptic activity, A levels in the brain gradually increases.  Harold D, Abraham R, Hollingworth P, et al. Genome-wide association study identifies variants atCLU and PICALM associated with Alzheimer’s disease. Nat Genet 41, 1088–93, (2009).  Lambert J-C, Heath S, Even G, et al. Genome-wide association study identifies variants at CLU andCR1 associated with Alzheimer’s disease. Nat Genet. 41, 1094–9, (2009). Sorkin, Alexander. "Cargo recognition during clathrin-mediated endocytosis: a team effort. Current opinion in cell biology 16 (4), 392-399, (2004). Goate, Alison, Marie-Christine Chartier-Harlin, et al. Segregation of a missense mutation in the amyloid precursor protein gene with familial Alzheimer's disease." Nature 349, 704, (1991).. Xiao Q, Gil SC, Yan P, et al. Role of Phosphatidylinositol Clathrin Assembly Lymphoid-Myeloid Leukemia (PICALM) in Intracellular Amyloid Precursor Protein (APP) Processing and Amyloid Plaque Pathogenesis. J Biol Chem287 (25), 21279-89. (2012).  Blondeau F, Ritter B, Allaire PD, et al. Tandem MS analysis of brain clathrin-coated vesicles reveals their critical involvement in synaptic vesicle recycling. Proc Natl Acad Sci U S A101 (11),  3833-8, (2004). Baig, S., S. Joseph, H. Tayler, et al. The distribution and expression of picalm in Alzheimer's disease. J Neuropathol Exp Neurol 69 (10), (2010). Zhao Z, Sagare A P, Ma Q, et al. Central role for PICALM in amyloid-β blood-brain barriertranscytosis and clearance. Nat Neurosci. 18 (7), (2015). Moreau K, Fleming A, Imarisio S, et al. PICALM modulates autophagy activity and tau accumulation. Nat Commun5, 4998, (2014).  Small, David H., Su San Mok, and Joel C. Bornstein. Alzheimer's disease and Aβ toxicity: from top to bottom. Nature Reviews Neuroscience 2 (8), 595, (2001). Treusch S, Hamamichi S, Goodman JL, et al. Functional links between Aβ toxicity, endocytic trafficking, and Alzheimer's disease risk factors in yeast. Science 334 (6060), 1241-5, (2011). Kanatsu K, Morohashi Y, Suzuki M, Kuroda H, Watanabe T, Tomita T, Iwatsubo T. DecreasedCALM expression reduces Aβ42 to total Aβ ratio through clathrin-mediated endocytosis of γ-secretase. Nat Commun. 2014 Feb 28;5:3386. PubMed. Nordstedt, C., Caporaso, G.L., Thyberg, J., Gandy, S.E., Greengard, P., Identification of the Alzheimer beta/A4 amyloid precursor protein in clathrin-coated vesicles purified from PC12 cells. J. Biol. Chem. 268 (1), 608–612. (1993).  Vassar, R., Bennett, B.D., Babu-Khan, S., et al. Beta-secretase cleavage of Alzheimer’s amyloid precursor protein by the transmembrane aspartic protease BACE. Science 286 (5440), 735–741, (1999). Poulsen, EbbeToftgaard, Agnete Larsen, et al. New insights to clathrin and adaptor protein 2 for the design and development of therapeutic strategies. International journal of molecular sciences 16 (12), 29446-29453, (2015).Congdon, Erin E., Jiaping Gu, Hameetha BR Sait, and Einar M. Sigurdsson. Antibody Uptake into Neurons Occurs Primarily via Clathrin Dependent Fcγ Receptor Endocytosis, and is a Prerequisite for Acute Tau Clearance. Journal of Biological Chemistry 288 (49), 35452-3465, (2013).Yao, Pamela J. "Synaptic frailty and clathrin-mediated synaptic vesicle trafficking in Alzheimer's disease." Trends in neurosciences 27 (1), 24-29, (2004).Schweizer, Felix E., and Timothy A. Ryan. The synaptic vesicle: cycle of exocytosis and endocytosis. Current opinion in neurobiology 16 (3), 298-304, (2006).Wu, Fangbai, and Pamela J. Yao. "Clathrin-mediated endocytosis and Alzheimer's disease: an update." Ageing research reviews 8 (3), 147-149, (2009). In AD individuals, the process of formation of various neurotransmitters like acetylcholine, which is responsible for declining the cognitive and learning process, and glutamate, which inhibit cellular communication and neuronal loss, decreases. Currently available drugs target these systems by controlling the breakdown of nicotinic acetylcholine chemical or changing the amount of brain chemical glutamate. These medicines show their impact on the patient for an average of 6 to 12 months, but often various side effects such as constipation, nausea, vomiting, fatigue, nausea, lack of appetite, weight loss, headache etc. are also seen. Use of these drugs is very cost effective too. The available medicines have failed in many clinical trials so far because they did select proper targets and species for therapeutic, and apart from these they had difficulty passing through the barriers between the neurons, infiltrate and interact with them. Therefore, various controversies arise from time to time on the effectiveness of drugs available for AD, but no conclusions have been reached yet. Currently, researchers have been looking for an effective therapeutic approach to reverse, cure and stabilize cognitive impairments in AD. Taly, Antoine, Pierre-Jean Corringer, Denis Guedin, Pierre Lestage, and Jean-Pierre Changeux. Nicotinic receptors: allosteric transitions and therapeutic targets in the nervous system. Nature reviews Drug discovery 8(9), 733, (2009).Kabbani, Nadine, Matthew P. Woll, Robert Levenson, Jon M. Lindstrom, and Jean-Pierre Changeux. Intracellular complexes of the β2 subunit of the nicotinic acetylcholine receptor in brain identified by proteomics. Proceedings of the National Academy of Sciences 104 (51), 20570-20575, (2007).  Schaaf, Christian P. Nicotinic acetylcholine receptors in human genetic disease. Genetics in Medicine 16 (9), 649, (2014). Fuchsberger, T., S. Martínez-Bellver, E. Giraldo, V. Teruel-Martí, A. Lloret, and J. Viña. Aβ induces excitotoxicity mediated by APC/C-Cdh1 depletion that can be prevented by glutaminase inhibition promoting neuronal survival. Scientific reports 6, 31158, (2016). Zoltowska, Katarzyna Marta, Masato Maesako, Joshua Meier, and Oksana Berezovska. Novel interaction between Alzheimer’s disease-related protein presenilin 1 and glutamate transporter 1. Scientific reports 8 (1), 8718, (2018). Casey, David A., Demetra Antimisiaris, and James O’Brien. Drugs for Alzheimer’s disease: are they effective?. Pharmacy and Therapeutics 35 (4), 208, (2010).1Supporting figure 1.Due to significant changes in the frequency ranges from 0.1 MHz to 1 GHz and 4 GHz to 5 GHz, the average power of CLC mixed beta amyloid in these regions was analyzed. A time-dependent study was also performed, which confirms the significant role of CLC in slowing down the effects of A over time. These results are presented in Figure 1 of the supporting material. The corresponding 3 D plots of average power spectrum of A mixed CLC with time in the same frequency regions are presented in Figure 2. Figure 1. 2 D Power spectrum plot of A, CLC and their interaction in the frequency ranges of 0.1 MHz to 1 GHz and from 5 to 6 GHz over time. In both plots, insets show that the intensity of ABeta mixed CLC gradually decreases over time.Supporting figure 2.Figure 2. 3-dimensional plot of average power spectrum of the interaction between ABeta and CLC with time in different frequency ranges (a). from 0.1 MHz to 1 GHz; (b). from 4 GHz to 5 GHz. image2.pngimage1.png