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A '''neurodegenerative disease''' is caused by the progressive loss
Within neurodegenerative diseases, it is estimated that 55 million people worldwide had [[dementia]] in 2019, and that by 2050 this figure will increase to 139 million people.<ref name="WHO dementia report">{{cite book |title=Global status report on the public health response to dementia. |date=2021 |publisher=World Health Organization |location=Geneva |isbn=978-92-4-003324-5 |url=https://apps.who.int/iris/bitstream/handle/10665/344701/9789240033245-eng.pdf |access-date=14 October 2022}}</ref>
==Specific disorders==
The consequences of neurodegeneration can vary widely depending on the specific region affected, ranging from issues related to movement to the development of dementia.<ref>{{Cite book |last1=Ovádi |first1=Judit |title=Protein folding and misfolding: neurodegenerative diseases |last2=Orosz |first2=Ferenc |date=2009 |publisher=Springer |isbn=978-1-4020-9434-7 |series=Focus on structural biology |location=Dordrecht, Netherlands, New York, London}}</ref><ref>{{Cite
===Alzheimer's disease===
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{{Main|Alzheimer's disease}}
[[Alzheimer's disease]] (AD) is a chronic neurodegenerative disease that results in the loss of [[neuron]]s and [[synapse]]s in the [[cerebral cortex]] and certain subcortical structures, resulting in gross [[atrophy]] of the [[temporal lobe]], [[parietal lobe]], and parts of the [[frontal cortex]] and [[cingulate gyrus]].<ref name="pmid12934968">{{cite journal | vauthors = Wenk GL | title = Neuropathologic changes in Alzheimer's disease | journal = The Journal of Clinical Psychiatry | volume = 64 | pages = 7–10 | year = 2003 | issue = Suppl 9 | pmid = 12934968 }}</ref> It is the most common neurodegenerative disease.<ref name=CSHPB-Apr18>{{cite journal|title=Clinical Neurology and Epidemiology of the Major Neurodegenerative Diseases|last1=Erkkinen|first1=Michael G.|last2=Kim|first2=Mee-Ohk|last3=Geschwind|first3=Michael D|journal=[[Cold Spring Harbor Perspectives in Biology]]|date=April 2018|volume=10|issue=4|page=20|doi=10.1101/cshperspect.a033118|pmid=28716886|pmc=5880171}}</ref> Even with billions of dollars being used to find a treatment for Alzheimer's disease, no effective treatments have been found.<ref>{{cite book| vauthors = Lock MM |url=https://www.worldcat.org/oclc/859536969|title=The Alzheimer conundrum : entanglements of dementia and aging|date=27 October 2013|isbn=978-1-4008-4846-1 |
AD pathology is primarily characterized by the presence of [[amyloid plaques]] and [[neurofibrillary tangle]]s. Plaques are made up of small [[peptide]]s, typically 39–43 amino acids in length, called [[amyloid beta]] (also written as A-beta or Aβ). Amyloid beta is a fragment from a larger protein called [[amyloid precursor protein]] (APP), a [[transmembrane protein]] that penetrates through the neuron's membrane. APP appears to play roles in normal neuron growth, survival and post-injury repair.<ref name="pmid16822978">{{cite journal | vauthors = Priller C, Bauer T, Mitteregger G, Krebs B, Kretzschmar HA, Herms J | title = Synapse formation and function is modulated by the amyloid precursor protein | journal = The Journal of Neuroscience | volume = 26 | issue = 27 | pages = 7212–21 | date = July 2006 | pmid = 16822978 | pmc = 6673945 | doi = 10.1523/JNEUROSCI.1450-06.2006 }}</ref><ref name="pmid12927332">{{cite journal | vauthors = Turner PR, O'Connor K, Tate WP, Abraham WC | title = Roles of amyloid precursor protein and its fragments in regulating neural activity, plasticity and memory | journal = Progress in Neurobiology | volume = 70 | issue = 1 | pages = 1–32 | date = May 2003 | pmid = 12927332 | doi = 10.1016/S0301-0082(03)00089-3 | s2cid = 25376584 }}</ref> APP is [[proteolysis|cleaved]] into smaller fragments by [[enzymes]] such as [[gamma secretase]] and [[beta secretase]].<ref name="pmid15787600">{{cite journal | vauthors = Hooper NM | title = Roles of proteolysis and lipid rafts in the processing of the amyloid precursor protein and prion protein | journal = Biochemical Society Transactions | volume = 33 | issue = Pt 2 | pages = 335–8 | date = April 2005 | pmid = 15787600 | doi = 10.1042/BST0330335 }}</ref> One of these fragments gives rise to fibrils of amyloid beta which can self-assemble into the dense extracellular amyloid plaques.<ref name="pmid15184601">{{cite journal | vauthors = Tiraboschi P, Hansen LA, Thal LJ, Corey-Bloom J | title = The importance of neuritic plaques and tangles to the development and evolution of AD | journal = Neurology | volume = 62 | issue = 11 | pages = 1984–9 | date = June 2004 | pmid = 15184601 | doi = 10.1212/01.WNL.0000129697.01779.0A | s2cid = 25017332 }}</ref><ref name="pmid15004691">{{cite journal | vauthors = Ohnishi S, Takano K | title = Amyloid fibrils from the viewpoint of protein folding | journal = Cellular and Molecular Life Sciences | volume = 61 | issue = 5 | pages = 511–524 | date = March 2004 | pmid = 15004691 | doi = 10.1007/s00018-003-3264-8 | s2cid = 25739126 | pmc = 11138910 }}</ref>
===Parkinson's disease===
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PD is primarily characterized by death of [[dopaminergic]] neurons in the [[substantia nigra]], a region of the [[midbrain]]. The cause of this selective cell death is unknown. Notably, [[alpha-synuclein]]-[[ubiquitin]] complexes and aggregates are observed to accumulate in [[Lewy bodies]] within affected neurons. It is thought that defects in protein transport machinery and regulation, such as [[RAB1]], may play a role in this disease mechanism.<ref>"Parkinson's Disease Mechanism Discovered," [http://www.hhmi.org/news/lindquist20060622.html HHMI Research News] June 22, 2006.</ref> Impaired axonal transport of alpha-synuclein may also lead to its accumulation in Lewy bodies. Experiments have revealed reduced transport rates of both wild-type and two familial Parkinson's disease-associated mutant alpha-synucleins through axons of cultured neurons.<ref name = devos /> Membrane damage by alpha-synuclein could be another Parkinson's disease mechanism.<ref name=curvature/>
The main known risk factor is age. Mutations in genes such as α-synuclein (SNCA), [[LRRK2|leucine-rich repeat kinase 2]] (LRRK2), [[glucocerebrosidase]] (GBA), and [[tau protein]] (MAPT) can also cause hereditary PD or increase PD risk.<ref name="pmid26601739">{{cite journal | vauthors = Davis AA, Andruska KM, Benitez BA, Racette BA, Perlmutter JS, Cruchaga C | title = Variants in GBA, SNCA, and MAPT influence Parkinson disease risk, age at onset, and progression | journal = Neurobiology of Aging | volume = 37 | pages = 209.e1–209.e7 | date = January 2016 | pmid = 26601739 | pmc = 4688052 | doi = 10.1016/j.neurobiolaging.2015.09.014 }}</ref> While PD is the second most common neurodegenerative disorder, problems with diagnoses still persist.<ref name="Schmidt-2020">{{Cite journal|last1=Schmidt|first1=Nele|last2=Paschen|first2=Laura|last3=Witt|first3=Karsten|date=2020-11-16|editor-last=Mirabella|editor-first=Giovanni|title=Invalid Self-Assessment of Olfactory Functioning in Parkinson's Disease Patients May Mislead the Neurologist|journal=Parkinson's Disease|language=en|volume=2020|pages=1–5|doi=10.1155/2020/7548394
===Huntington's disease===
{{Main|Huntington's disease}}
[[Huntington's disease]] (HD) is a rare [[autosomal dominant]] neurodegenerative disorder caused by mutations in the [[huntingtin gene]] ''(HTT)''. HD is characterized by loss of [[medium spiny neuron]]s and [[astrogliosis]].<ref>{{cite book |vauthors=Purves D, Augustine GA, Fitzpatrick D, Hall W, LaMantia AS, McNamara JO, Williams SM |
HD is caused by [[polyglutamine tract]] expansion in the huntingtin gene, resulting in the mutant huntingtin. Aggregates of mutant huntingtin form as [[inclusion bodies]] in neurons, and may be directly toxic. Additionally, they may damage molecular motors and microtubules to interfere with normal [[axonal transport]], leading to impaired transport of important cargoes such as [[BDNF]].<ref name = devos /> Huntington's disease currently has no effective treatments that would modify the disease.<ref>{{cite journal | vauthors = Labbadia J, Morimoto RI | title = Huntington's disease: underlying molecular mechanisms and emerging concepts | journal = Trends in Biochemical Sciences | volume = 38 | issue = 8 | pages = 378–85 | date = August 2013 | pmid = 23768628 | pmc = 3955166 | doi = 10.1016/j.tibs.2013.05.003 }}</ref>
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=== Multiple sclerosis ===
{{Main|Multiple sclerosis}}
[[Multiple sclerosis]] (MS) is a chronic debilitating [[demyelinating disease]] of the [[central nervous system]], caused by an autoimmune attack resulting in the progressive loss of myelin sheath on neuronal axons.<ref name="ninds.nih.gov">{{Cite web|title=Multiple Sclerosis: Hope Through Research {{!}} National Institute of Neurological Disorders and Stroke|url=https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Hope-Through-Research/Multiple-Sclerosis-Hope-Through-Research|access-date=2020-11-30|website=www.ninds.nih.gov}}</ref> The resultant decrease in the speed of signal transduction leads to a loss of functionality that includes both cognitive and motor impairment depending on the location of the lesion.<ref name="ninds.nih.gov"/> The progression of MS occurs due to episodes of increasing inflammation, which is proposed to be due to the release of antigens such as [[myelin oligodendrocyte glycoprotein]], [[myelin basic protein]], and [[proteolipid protein]], causing an autoimmune response.<ref>{{Citation|last1=Kaufman|first1=David Myland|title=Chapter 15 - Multiple Sclerosis|date=2013-01-01|url=http://www.sciencedirect.com/science/article/pii/B9780723437482000153|work=Kaufman's Clinical Neurology for Psychiatrists (Seventh Edition)|pages=329–349|editor-last=Kaufman|editor-first=David Myland|place=Philadelphia|publisher=W.B. Saunders|language=en|isbn=978-0-7234-3748-2|access-date=2020-12-07|last2=Milstein|first2=Mark J.|editor2-last=Milstein|editor2-first=Mark J.}}</ref> This sets off a cascade of signaling molecules that result in T cells, B cells, and [[macrophage]]s to cross the blood-brain barrier and attack myelin on neuronal axons leading to inflammation.<ref name="Stys-2019"/> Further release of antigens drives subsequent degeneration causing increased inflammation.<ref>{{cite journal | doi=10.1093/brain/awn080 | title=Remyelination protects axons from demyelination-associated axon degeneration | year=2008 | last1=Irvine | first1=K. A. | last2=Blakemore | first2=W. F. | journal=Brain | volume=131 | issue=6 | pages=
===Amyotrophic lateral sclerosis===
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===Batten disease===
{{Main|Batten disease}}
[[Batten disease]] is a rare and fatal recessive neurodegenerative disorder that begins in childhood.<ref name="NIH">{{cite web |title=Batten Disease Fact Sheet {{!}} National Institute of Neurological Disorders and Stroke |url=https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Batten-Disease-Fact-Sheet |website=www.ninds.nih.gov |access-date=30 November 2020}}</ref> Batten disease is the common name for a group of [[lysosomal storage disorder]]s known as [[neuronal ceroid lipofuscinosis|neuronal ceroid lipofuscinoses]] (NCLs) – each caused by a specific gene mutation,<ref name="NIH" /> of which there are thirteen.<ref name=
=== Creutzfeldt–Jakob disease ===
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[[Creutzfeldt–Jakob disease]] (CJD) is a [[prion]] disease that is characterized by rapidly progressive dementia.<ref>{{cite web |title=Creutzfeldt-Jakob Disease Fact Sheet {{!}} National Institute of Neurological Disorders and Stroke |url=https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Creutzfeldt-Jakob-Disease-Fact-Sheet |website=www.ninds.nih.gov |publisher=National Institute of Health |access-date=31 March 2022}}</ref> Misfolded proteins called prions aggregate in brain tissue leading to nerve cell death.<ref>{{cite web |title=Creutzfeldt-Jakob disease - Symptoms and causes |url=https://www.mayoclinic.org/diseases-conditions/creutzfeldt-jakob-disease/symptoms-causes/syc-20371226 |website=Mayo Clinic |access-date=31 March 2022 |language=en}}</ref> [[Variant Creutzfeldt–Jakob disease]] (vCJD) is the infectious form that comes from the meat of a cow that was infected with [[bovine spongiform encephalopathy]], also called mad cow disease.<ref>{{cite web |last1=Research |first1=Center for Biologics Evaluation and |title=Variant Creutzfeldt-Jakob Disease (vCJD) and Factor VIII (pdFVIII) Questions and Answers |url=https://www.fda.gov/vaccines-blood-biologics/safety-availability-biologics/variant-creutzfeldt-jakob-disease-vcjd-and-factor-viii-pdfviii-questions-and-answers |website=FDA |access-date=31 March 2022 |language=en |date=12 April 2019}}</ref>
==Risk
===Aging===
{{Further|Aging brain}}
The greatest risk factor for neurodegenerative diseases is [[ageing|aging]]. [[Free-radical theory of aging#Mitochondria|Mitochondrial DNA mutations]] as well as [[oxidative stress]] both contribute to aging.<ref name = lin /> Many of these diseases are late-onset, meaning there is some factor that changes as a person ages for each disease.<ref name="rubinsztein"/> One constant factor is that in each disease, neurons gradually lose function as the disease progresses with age. It has been proposed that [[DNA damage (naturally occurring)|DNA damage]] accumulation provides the underlying causative link between aging and neurodegenerative disease.<ref name= Bernsteinbook>{{cite book | vauthors = Bernstein C, Bernstein H | date = 1991 | title = Aging, Sex, and DNA Repair | pages = 121–139 | publisher = Academic Press | location = San Diego | isbn = 978-
===Infections===
[[File:Hazard ratio lag for replicated viral infection–neurodegenerative disease pairs.jpg|thumb|180px|Risks from viral exposures according to one biobank study<ref name="10.1016/j.neuron.2022.12.029"/>]]
A study using [[electronic health record]]s indicates that 45 (with 22 of these being replicated with the [[UK Biobank]]) viral exposures can significantly elevate risks of neurodegenerative disease, including up to 15 years after infection.<ref name="10.1016/j.neuron.2022.12.029">{{cite journal |last1=Levine |first1=Kristin S. |last2=Leonard |first2=Hampton L. |last3=Blauwendraat |first3=Cornelis |last4=Iwaki |first4=Hirotaka |last5=Johnson |first5=Nicholas |last6=Bandres-Ciga |first6=Sara |last7=Ferrucci |first7=Luigi |last8=Faghri |first8=Faraz |last9=Singleton |first9=Andrew B. |last10=Nalls |first10=Mike A. |title=Virus exposure and neurodegenerative disease risk across national biobanks |journal=Neuron |date=19 January 2023 |volume=111 |issue=7 |pages=
* News article about the study: {{cite journal |last1=Kozlov |first1=Max |title=Massive health-record review links viral illnesses to brain disease |url=https://www.nature.com/articles/d41586-023-00181-3 |access-date=15 February 2023 |journal=Nature |date=23 January 2023 |volume=614 |issue=7946 |pages=18–19 |language=en |doi=10.1038/d41586-023-00181-3 |pmid=36690772 |bibcode=2023Natur.614...18K |s2cid=256193462 |archive-date=6 February 2023 |archive-url=https://web.archive.org/web/20230206084328/https://www.nature.com/articles/d41586-023-00181-3 |url-status=live |url-access=subscription }}</ref><ref>{{Cite journal |last1=Leblanc |first1=Pascal |last2=Vorberg |first2=Ina Maja |date=2022-08-04 |title=Viruses in neurodegenerative diseases: More than just suspects in crimes |journal=PLOS Pathogens |language=en |volume=18 |issue=8 |pages=e1010670 |doi=10.1371/journal.ppat.1010670 |doi-access=free
==Mechanisms==
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=== Epigenetics ===
The presence of epigenetic modifications for certain genes has been demonstrated in this type of pathology. An example is [[FKBP5]] gene, which progressively increases its expression with age and has been related to [[Braak staging]] and increased tau pathology both in vitro and in mouse models of AD.<ref>{{Cite journal|last1=Nabais|first1=Marta F.|last2=Laws|first2=Simon M.|last3=Lin|first3=Tian|last4=Vallerga|first4=Costanza L.|last5=Armstrong|first5=Nicola J.|last6=Blair|first6=Ian P.|last7=Kwok|first7=John B.|last8=Mather|first8=Karen A.|last9=Mellick|first9=George D.|last10=Sachdev|first10=Perminder S.|last11=Wallace|first11=Leanne|date=2021-03-26|title=Meta-analysis of genome-wide DNA methylation identifies shared associations across neurodegenerative disorders|journal=Genome Biology|volume=22|issue=1|pages=90|doi=10.1186/s13059-021-02275-5
===Protein misfolding===
{{See also|Stress granule}}
Several neurodegenerative diseases are classified as [[proteopathy|proteopathies]] as they are associated with the [[protein aggregation|aggregation]] of [[protein folding|misfolded proteins]]. Protein toxicity is one of the key mechanisms of many neurodegenrative diseases.<ref name="Chung">{{cite journal |last1=Chung |first1=CG |last2=Lee |first2=H |last3=Lee |first3=SB |title=Mechanisms of protein toxicity in neurodegenerative diseases. |journal=Cellular and Molecular Life Sciences |date=September 2018 |volume=75 |issue=17 |pages=
* '''[[alpha-synuclein]]:''' can aggregate to form insoluble fibrils in pathological conditions characterized by [[Lewy bodies]], such as Parkinson's disease, [[dementia with Lewy bodies]], and [[multiple system atrophy]]. Alpha-synuclein is the primary structural component of Lewy body fibrils. In addition, an alpha-synuclein fragment, known as the non-Abeta component (NAC), is found in [[amyloid plaques]] in [[Alzheimer's disease]].
* '''[[Tau protein|tau]]:''' [[hyperphosphorylated]] [[tau protein]] is the main component of [[neurofibrillary tangles]] in Alzheimer's disease; tau fibrils are the main component of [[Pick bodies]] found in [[behavioral variant frontotemporal dementia]].
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====Axonal transport====
{{Main|Axonal transport}}
Axonal swelling, and [[axonal spheroid]]s have been observed in many different neurodegenerative diseases. This suggests that defective axons are not only present in diseased neurons, but also that they may cause certain pathological insult due to accumulation of organelles. [[Axonal transport]] can be disrupted by a variety of mechanisms including damage to: [[kinesin]] and [[cytoplasmic dynein]], [[microtubules]], cargoes, and [[mitochondria]].<ref name = devos>{{cite journal | vauthors = De Vos KJ, Grierson AJ, Ackerley S, Miller CC | title = Role of axonal transport in neurodegenerative diseases | journal = Annual Review of Neuroscience | volume = 31 | pages = 151–73 | year = 2008 | pmid = 18558852 | doi = 10.1146/annurev.neuro.31.061307.090711 }}</ref> When axonal transport is severely disrupted a degenerative pathway known as [[Wallerian degeneration|Wallerian-like degeneration]] is often triggered.<ref>{{cite journal |vauthors=Coleman MP
===Programmed cell death===
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===Animal models in research===
In the search for effective treatments (as opposed to [[palliative care]]), investigators employ [[animal model]]s of disease to test potential therapeutic agents. Model organisms provide an inexpensive and relatively quick means to perform two main functions: target identification and target validation. Together, these help show the value of any specific therapeutic strategies and drugs when attempting to ameliorate disease severity. An example is the drug [[Dimebon]] by Medivation, Inc. In 2009 this drug was in phase III clinical trials for use in Alzheimer's disease, and also phase II clinical trials for use in Huntington's disease.<ref name = marsh /> In March 2010, the results of a clinical trial phase III were released; the investigational Alzheimer's disease drug Dimebon failed in the pivotal CONNECTION trial of patients with mild-to-moderate disease.<ref>
[http://www.alzforum.org/new/detail.asp?id=2387 Dimebon Disappoints in Phase 3 Trial]</ref> With CONCERT, the remaining Pfizer and Medivation Phase III trial for Dimebon (latrepirdine) in Alzheimer's disease failed in 2012, effectively ending the development in this indication.<ref name=
In another experiment using a rat model of Alzheimer's disease, it was demonstrated that systemic administration of hypothalamic proline-rich peptide (PRP)-1 offers neuroprotective effects and can prevent neurodegeneration in hippocampus [[amyloid-beta]] 25–35. This suggests that there could be therapeutic value to PRP-1.<ref name = galoyan>{{cite journal | vauthors = Galoyan AA, Sarkissian JS, Chavushyan VA, Meliksetyan IB, Avagyan ZE, Poghosyan MV, Vahradyan HG, Mkrtchian HH, Abrahamyan DO | display-authors = 6 | title = Neuroprotection by hypothalamic peptide proline-rich peptide-1 in Abeta25-35 model of Alzheimer's disease | journal = Alzheimer's & Dementia | volume = 4 | issue = 5 | pages = 332–44 | date = September 2008 | pmid = 18790460 | doi = 10.1016/j.jalz.2007.10.019 | s2cid = 39817779 }}</ref>
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== References ==
{{Reflist}}
{{Medical resources
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