Facebook PixelA list of brain junk substances that build up with age
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A list of brain junk substances that build up with age

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Darko Savic
Darko Savic Nov 24, 2020
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What are all the known intracellular and extracellular substances that build up with age and clog the brain?

Before we think about solutions we should understand what we are dealing with. Such a list could help us appreciate the magnitude and diversity of the problem of the intracellular and extracellular brain junk accumulation.
aging longevity
9
Creative contributions

Lipofuscin

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Shubhankar Kulkarni
Shubhankar Kulkarni Nov 24, 2020
Lipofuscin is the fine yellow-brown pigment granule composed of residues of lysosomal digestion. It is one of the aging pigments, found in the nerve and ganglion cells. It may be due to damage to mitochondria and lysosomes. The pathological accumulation of lipofuscin is implicated in Alzheimer's disease, Parkinson's disease, and acromegaly.
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Tau protein

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Subash Chapagain
Subash Chapagain Nov 24, 2020
pTau (phosphorylated tau) proteins are constituents of NFTs (Neurofibrillary Tangles)- the protein aggregates that are commonly seen in brain regions that are affected by Alzheimer's Disease, namely cortical areas, isocortex, entorhinal region and hippocampus. Abnormally folded/modified forms of Tau protein are aggregated in NFTS as well as neutrophil threads and neuritic plaques .

Not just in neuronal cells, tau protein accumulation has been attributed to clinical conditions in non-neuronal cells as well. In this recent study, it was found that accumulation of tau in hilar astrocytes of dentate gyrus of patients of AD. When 3R tau was overexpressed in mice hilar astrocytes, it altered mitochondrial dynamics and function. These tau accumulation associated aberrations are deemed to cause reduction in adult neurogenesis, parvalbumin-expressing neurons, inhibitory synapses and hilar gamma oscillations accompanied by impaired spatial memory performances. This indicates that the loss of tau homeostasis (preferably by over accumulation) in hilar astrocytes of the dentate gyrus is sufficient to induce symptoms similar to that of AD through the impairment of neuronal network .


[1]https://www.sciencedirect.com/topics/neuroscience/tau-protein

[2]https://www.nature.com/articles/s41593-020-00728-x#:~:text=Alzheimer's%20disease%20(AD)%20is%20characterized,neurons%2C%20neurodegeneration%20and%20memory%20loss.&text=These%20results%20are%20important%20for,of%20astrocytes%20in%20hippocampal%20function.

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Dysfunctional mitochondria

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Shubhankar Kulkarni
Shubhankar Kulkarni Nov 24, 2020
The decline in the mitochondrial function with age (mitochondrial enlargement or fragmentation, oxidative damage, impaired electron transport chain function, increased number of mitochondria with depolarized membranes, impaired Ca2+ handling, and a reduced threshold for initiating the formation of mitochondrial membrane permeability transition pores) is observed. Most brain cell types accumulate dysfunctional mitochondria during aging.

[1]Mattson MP, Arumugam TV. Hallmarks of Brain Aging: Adaptive and Pathological Modification by Metabolic States. Cell Metab. 2018;27(6):1176-1199. doi:10.1016/j.cmet.2018.05.011

[2]Lin DT, Wu J, Holstein D, Upadhyay G, Rourk W, Muller E, Lechleiter JD. Ca2+ signaling, mitochondria and sensitivity to oxidative stress in aging astrocytes. Neurobiol Aging. 2007 Jan;28(1):99-111. doi: 10.1016/j.neurobiolaging.2005.11.004. Epub 2005 Dec 15. PMID: 16359757.

[3]Ghosh D, LeVault KR, Barnett AJ, Brewer GJ. A reversible early oxidized redox state that precedes macromolecular ROS damage in aging nontransgenic and 3xTg-AD mouse neurons. J Neurosci. 2012 Apr 25;32(17):5821-32. doi: 10.1523/JNEUROSCI.6192-11.2012. PMID: 22539844; PMCID: PMC3376759.

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Damaged oxidants

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Shubhankar Kulkarni
Shubhankar Kulkarni Nov 24, 2020
Neurons accumulate dysfunctional proteins and mitochondria due to an oxidative imbalance - increased reactive oxygen species (superoxide anion radical, hydroxyl radical, and nitric oxide) and/or reduced antioxidant defenses.

Carbonylated proteins in neurons and astrocytes and nitrated proteins in blood vessels lead to decreased olfactory functions. Aberrant nitric oxide-mediated oxidative damage leads to vascular dysfunction. Old animal brains accumulate the lipid peroxidation product 4-hydroxynonenal, associated with amyloid deposits and neurofibrillary tangles. Nitric oxide and 4-hydroxynonenal modify and impair the function of proteins involved in cell metabolism and survival.

Oxidatively modified and damaged proteins are degraded by proteasomes (ubiquitination) and lysosomes (autophagy). However, excessive oxidative stress can impair the function of proteasomes and lysosomes.

[1]Mattson MP, Arumugam TV. Hallmarks of Brain Aging: Adaptive and Pathological Modification by Metabolic States. Cell Metab. 2018;27(6):1176-1199. doi:10.1016/j.cmet.2018.05.011

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Iron (Fe) accumulation

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Subash Chapagain
Subash Chapagain Nov 24, 2020
Deposition of Fe in the human brain has been reported in a number of acquired and genetic neurologic disorders, and considered as a factor that contributes to the pathogenesis of some neuro-degenerative diseases. One such example is in the case of hemochromatosis, an autosomal recessively inherited disorder encoded by a gene associated with particular HLA subtypes.
A distinct group of syndromes referred to as Neurodegeneration with Brain Iron Accumulation (NBIA) comprises of conditions of iron deposition that lead to mixed extrapyramidal features and progressive dementia. Though there has not been any definitive identifiable molecular cause for NBIA, discoveries have shown that mutations in C19orf12 (Chromosome 19 Open Reading Frame 12) or WDR45 can lead to NBIA . C19orf12 mutations are recessively inherited, and they lead to a syndrome similar to that caused by PANK2 or PLA2G6 mutations (that are disorders related to mitochondrial membrane protein). WDR45 mutations are different in that they lead to a distinct form of NBIA characterized by spasticity and intellectual disability in childhood followed by onset of dystonia-parkinsonism in adulthood. These mutations are X-linked and dominant.

[1]https://link.springer.com/chapter/10.1007/978-3-7091-9322-8_2

[2]Doorn, J.M., Kruer, M.C. Newly Characterized Forms of Neurodegeneration with Brain Iron Accumulation. Curr Neurol Neurosci Rep 13, 413 (2013). https://doi.org/10.1007/s11910-013-0413-9

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Ceramide

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Shubhankar Kulkarni
Shubhankar Kulkarni Nov 25, 2020
Increased levels of low-density lipoproteins and triglycerides in the blood are risk factors for stroke, dementia, and Alzeimer's disease. Brain dyslipidemia is altered metabolism of multiple lipid species during aging. Accumulation of long-chain ceramides and lipid-laden cells is observed.

[1]Appleton JP, Scutt P, Sprigg N, Bath PM. Hypercholesterolaemia and vascular dementia. Clin Sci (Lond). 2017 Jun 30;131(14):1561-1578. doi: 10.1042/CS20160382. PMID: 28667059.

[2]Cutler RG, Kelly J, Storie K, Pedersen WA, Tammara A, Hatanpaa K, Troncoso JC, Mattson MP. Involvement of oxidative stress-induced abnormalities in ceramide and cholesterol metabolism in brain aging and Alzheimer's disease. Proc Natl Acad Sci U S A. 2004 Feb 17;101(7):2070-5. doi: 10.1073/pnas.0305799101. Epub 2004 Feb 15. PMID: 14970312; PMCID: PMC357053.

[3]Shimabukuro MK, Langhi LG, Cordeiro I, Brito JM, Batista CM, Mattson MP, Mello Coelho Vd. Lipid-laden cells differentially distributed in the aging brain are functionally active and correspond to distinct phenotypes. Sci Rep. 2016 Mar 31;6:23795. doi: 10.1038/srep23795. PMID: 27029648; PMCID: PMC4814830.

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Neurotoxic forms of α-synuclein

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Shubhankar Kulkarni
Shubhankar Kulkarni Nov 25, 2020
In Parkinson's diseae, aging results in the intracellular accumulation of neurotoxic forms of α-synuclein, and the accumulation of α-synuclein further aggravates the aging processes leading to neuronal dysfunction and death.

[1]Mattson MP, Arumugam TV. Hallmarks of Brain Aging: Adaptive and Pathological Modification by Metabolic States. Cell Metab. 2018;27(6):1176-1199. doi:10.1016/j.cmet.2018.05.011

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TDP-43

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Jamila
Jamila Nov 25, 2020
TDP-43 aggregates are characteristically seen in those at an advanced age with Alzheimer's disease, hippocampal sclerosis, and ALS. Higher levels of TDP-43 inclusions have been associated with rapid cognitive impairment in older individuals.

[1]Zhang, Lumi, et al. "TDP-43 and Limbic-Predominant Age-Related TDP-43 Encephalopathy." Frontiers in Aging Neuroscience 11 (2020): 376.

[2]Wilson, Robert S., et al. "TDP-43 pathology, cognitive decline, and dementia in old age." JAMA neurology 70.11 (2013): 1418-1424.

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Amyloid beta

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Darko Savic
Darko Savic Nov 24, 2020
Misfolding and aggregation of the otherwise soluble amyloid-beta peptides into beta-sheet-rich oligomeric structures that have a neurotoxic activity and ability to form insoluble amyloid deposits that accumulate in the brain. This is thought to be the leading cause of Alzheimer's disease.

[1]Soto C, Estrada L. Amyloid inhibitors and beta-sheet breakers. Subcell Biochem. 2005;38:351-64. doi: 10.1007/0-387-23226-5_18. PMID: 15709488.

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General comments

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Darko Savic
Darko Savic4 years ago
Here are two cool sessions that focus on junk clearance:
https://brainstorming.com/r/s19
https://brainstorming.com/r/s33
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