Beta amyloid

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Beta amyloid
Beta amyloid
Rod / ribbon model of Aβ42; according to PDB  1IYT
Mass / length primary structure 40/42 amino acids
Precursor Amyloid precursor protein
Identifier
Gene name (s) Abeta40, Abeta42
External IDs
Transporter classification
TCDB 1.C.50
designation ABPP
Occurrence
Homology family Beta amyloid
Parent taxon Vertebrates

Cleavage of the APP by α-, β- and γ-secretase (s)

β-amyloid (including amyloid-beta 40 (Aβ40) and amyloid-beta 42 (Aβ42) ) are peptides that are produced by cutting the amyloid precursor protein (APP) with the help of the enzymes beta and gamma secretase , although these are other factors must also be present. Since mainly N-terminally shortened peptides are found in senile plaques in particular (e.g. Aβ4-42, Aβ2-42), further proteases must be involved. Their biological function is unclear, but it has been suggested that they have an antimicrobial function . Aβ40 and Aβ42 are considered to be neurotoxic . In particular, the peptides derived from Aβ42 have a strong tendency to stick to each other and to form aggregates of different sizes, which can also be insoluble. In normal metabolism , these peptides are produced continuously, but are not deposited. Both peptides can be found as deposits in the brain and blood vessels of Alzheimer's disease and Down syndrome patients. It is believed, therefore, that preventing these deposits (including senile plaques) would improve the symptoms of these diseases.

In a new study it was shown that beta-amyloid is deposited in the brain even after a severe head trauma . Interestingly, it is not the lesion that is primarily affected by the deposits , but rather other areas of the brain, especially the striatum . There are also frequent changes in Alzheimer's disease . However, a connection between severe head trauma and later dementia has not yet been proven.

A scientific study has shown that amyloid beta has a central function in information processing in the brain. A certain amount of the protein is necessary for the transmission of information to neurons. Since current research into the fight against Alzheimer's is mainly focused on developing drugs that break down protein plaques, this new finding needs to be taken into account.

Reasons for increased Aβ levels

Further factors for the changes in Aβ40 / 42 are genetic predispositions, such as

  • Change of APP by mutation of the APP - gene (familial Alzheimer type 1)
  • Presence of certain alleles of apolipoprotein E (familial Alzheimer's type 2).
  • Changes in gamma secretase in its presenilin subunits (types 3 and 4)
  • increased production of the APP, as in Down syndrome

These rare changes in the genome alone can be enough to cause Aβ in sufficient quantities and thus to cause damage.

In addition, there are diet-related risk factors such as cholesterol levels : if there is a cholesterol deficiency, beta-amyloid peptides are not formed in vitro . This may have something to do with the fact that Aβ production takes place exclusively in so-called lipid rafts of the cell membrane, and that these structures consist primarily of cholesterol.

However, there appear to be other risk factors. Several drugs increase Aβ42 production to dangerous levels in vitro and in the mouse model. Specific inhibitors for cyclooxygenase 2 and certain isoprenoids are suspected .

toxicity

There are several attempts to explain the mechanism of the neurotoxicity of the peptides. On the one hand, the peptides could form ion channels in the cell membrane of the neurons . It is possible, however, that these are small but numerous membrane defects that are caused by amyloids and are responsible for the damage.

Individual evidence

  1. Jump up ↑ Soscia SJ, Kirby JE, Washicosky KJ, Tucker SM, Ingelsson M, et al. (2010): The Alzheimer's Disease-Associated Amyloid β-Protein Is an Antimicrobial Peptide. PLoS ONE 5 (3): e9505. doi : 10.1371 / journal.pone.0009505
  2. ↑ a b UniProt P05067
  3. ↑ Masters CL, Simms G, Weinman NA, Multhaup G, McDonald BL, Beyreuther K: Amyloid plaque core protein in Alzheimer's disease and Down syndrome . In: Proc. Natl. Acad. Sci. USA . 82, No. 12, June 1985, pp. 4245-9. PMID 3159021 . PMC 397973 (free full text).
  4. ↑ Young T. Hong, Tonny Veenith, Deborah Dewar, Joanne G. Outtrim, Vaithianadan Mani, Claire Williams, Sally Pimlott, Peter JA Hutchinson, Adriana Tavares, Roberto Canales, Chester A. Mathis, William E. Klunk, Franklin I. Aigbirhio , Jonathan P. Coles, Jean-Claude Baron, John D. Pickard, Tim D. Fryer, William Stewart, David K. Menon: Amyloid Imaging With Carbon 11-Labeled Pittsburgh Compound B for Traumatic Brain Injury. In: JAMA Neurology. , S., doi : 10.1001 / jamaneurol.2013.4847 .
  5. ↑ ScienceDaily: Alzheimer's: Destructive Amyloid-Beta Protein May Also Be Essential for Normal Brain Function (accessed November 25, 2009).
  6. ↑ Abramov et al .: Amyloid-β as a positive endogenous regulator of release probability at hippocampal synapses Nature Neuroscience , 2009; doi : 10.1038 / nn.2433
  7. ↑ UniProt P02649
  8. ↑ Strittmatter WJ, Weisgraber KH, Huang DY, et al : Binding of human apolipoprotein E to synthetic amyloid beta peptide: isoform-specific effects and implications for late-onset Alzheimer disease . In: Proc. Natl. Acad. Sci. USA . 90, No. 17, September 1993, pp. 8098-102. PMID 8367470 . PMC 47295 (free full text).
  9. ↑ UniProt P49768 , UniProt P49810
  10. ↑ Simons M, Keller P, De Strooper B, Beyreuther K, Dotti CG, Simons K: Cholesterol depletion inhibits the generation of beta-amyloid in hippocampal neurons . In: Proc. Natl. Acad. Sci. USA . 95, No. 11, May 1998, pp. 6460-4. PMID 9600988 . PMC 27798 (free full text).
  11. ↑ Cordy JM, Hussain I, Dingwall C, Hooper NM, Turner AJ: Exclusively targeting beta-secretase to lipid rafts by GPI-anchor addition up-regulates beta-site processing of the amyloid precursor protein . In: Proc. Natl. Acad. Sci. USA . 100, No. 20, September 2003, pp. 11735-40. doi : 10.1073 / pnas.1635130100 . PMID 14504402 . PMC 208827 (free full text).
  12. ↑ Fassbender K, Simons M, Bergmann C, et al : Simvastatin strongly reduces levels of Alzheimer's disease beta -amyloid peptides Abeta 42 and Abeta 40 in vitro and in vivo . In: Proc. Natl. Acad. Sci. USA . 98, No. 10, May 2001, pp. 5856-61. doi : 10.1073 / pnas.081620098 . PMID 11296263 . PMC 33303 (free full text).
  13. ↑ Kukar T, Murphy MP, Eriksen JL, et al : Diverse compounds mimic Alzheimer disease-causing mutations by augmenting Abeta42 production . In: Nat. Med. . 11, No. 5, May 2005, pp. 545-50. doi : 10.1038 / nm1235 . PMID 15834426 .
  14. ↑ TCDB : 1.C.50
  15. ↑ Green JD, Kreplak L, Goldsbury C, et al : Atomic force microscopy reveals defects within mica supported lipid bilayers induced by the amyloidogenic human amylin peptide . In: J. Mol. Biol. . 342, No. 3, September 2004, pp. 877-87. doi : 10.1016 / j.jmb.2004.07.052 . PMID 15342243 .