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Definition
Alzheimer’s disease (AD) is one of the most common forms of senile dementia, whose pathogenetic basis is related to the presence of amyloid ß-peptide (Aß), a ß-sheet peptide formed by 39–43-amino acid residues that aggregates in the brain to form the major component of characteristic deposits known as senile plaques.

Discovery
Histopathological studies of affected brain regions in AD patients typically show neurofibrillary tangles (NFTs) in both dying and already degenerated neurons and senile plaques. The senile plaques are often surrounded by dystrophic neurites, activated microglia and reactive astrocytes. The major protein component of the core of the senile plaques is Aß, a 39±43 amino acid-long peptide derived from the larger amyloid b-protein precursor (APP), a ubiquitously expressed transmembrane glycoprotein, as shown by Glenner and Wong, 1984 1.

Structural Characteristics
Aß is formed after sequential cleavage of the amyloid precursor protein, a transmembrane glycoprotein of undetermined function. The ? secretase, which produces the C-terminal end of the Aß peptide, cleaves within the transmembrane region of APP and can generate a number of isoforms of 39-43 amino acid residues in length. The 40-amino acid form of Aß (Aß40) accounts for ˜90% of all Aß normally released from cells, it appears to contribute only to later phases of the pathology. In contrast, the longer more amyloidogenic 42-residue form (Aß42), accounting for only ˜10% of secreted Aß, is deposited in the earliest phase of AD and remains the major constituent of most amyloid plaques throughout the disease. Moreover, its levels have been shown to be increased in all known forms of early-onset familial AD. Aß fragment 25-35 and Aß fragment 31-35, dose-dependently potentiate long term depression 2.

Mode of Action

Aß (31–35) and Aß (25–35) fragments of amyloid beta-protein induce cellular death through apoptotic signals: Exposure of isolated rat brain mitochondria to Aß(31–35) and Aß(25–35) peptides determine release of cytochrome c; mitochondrial swelling and a significant reduction in mitochondrial oxygen consumption. In contrast, the amplitude of these events, the isolated brain mitochondria exposed to the Aß(31–35)Met35, the methionine-35 was oxidized to methionine sulfoxide3. Taken together our result indicate that Aß(31–35) and Aß(25–35) peptides in non-aggregated form, i.e., predominantly monomeric, are strongly neurotoxic, having the ability to enter within the cells, determining mitochondrial damage with an evident trigger of apoptotic signals.

Functions

Oxidative Stress and Neurotoxicity for Alzheimer’s Aß(1-42) and Aß(25-35): The mechanism by which the predominant form of Aß found in AD brains, Aß(1-42), causes oxidative stress and neurotoxicity remains unknown. Numerous laboratories have used the smaller 11-amino acid fragment of the full-length peptide, Aß(25-35), as a convenient alternative in AD investigations since the smaller peptide mimics several of the toxicological and oxidative stress properties of the native full-length peptide.The studies reveal that two different mechanisms may be operative in the two peptides; however, the single methionine residue in the peptides appears to play a crucial role in both mechanisms. That methionine is C-terminal in Aß(25-35) seems to be the cause for its exaggerated effects. When the next amino acid in the sequence of Aß(1-42) (valine) is appended to Aß(25-35), the resultant peptide, Aß(25-36), in which methionine is no longer C-terminal, is neither toxic to cultured neuron nor does it cause oxidative damage4. Additionally, oxidizing the sulfur of methionine to a sulfoxide abrogates the damaging effects of both Aß(25-35) and Aß(1-42).

ß-amyloid peptide fragment 31–35 induces apoptosis in cultured cortical neurons: In a study, a synthetic fragment 31–35 of ß-amyloid peptide was used in cultured cortical neurons to examine whether this smaller sequence could trigger apoptotic degeneration in vitro by using morphological, biochemical and flow-cytometric examinations. The results showed that: neurons treated with fragment 31–35 of ß-amyloid peptide exhibited membrane blebbing, compaction of nuclear chromatin, nuclear shrinkage and nuclear fragmentation; a typical DNA ladder was revealed by agarose gel electrophoresis following fragment 31–35 of ß-amyloid peptide exposure. Furthermore, the internucleosome DNA fragmentation was also detected by flow-cytometric examination following fragment 31–35 of ß-amyloid peptide exposure; and the DNA fragmentation induced by fragment 31–35 of ß-amyloid peptide could be blocked by co-treatment with aurintricarboxylic acid or actinomycin D. It is suggested that fragment 31–35 of the ß-amyloid peptide may be a shorter sequence of ß-amyloid peptide responsible for triggering an apoptotic process in cultured neurons5.

References

  1. Glenner GG, Wong CW (1984). Alzheimer’s disease: initial report of the purification and characterization of a novel cerebrovascular amyloid protein. Biochem. Biophys. Res. Commun., 120:885-890.
  2. Cheng L, Yin WJ, Zhang JF, Qi JS (2009). Amyloid ß -protein fragments 25-35 and 31-35 potentiate long-term depression in hippocampal CA1 region of rats in vivo. Synapse., 63:206-214.
  3. Clementi ME, Marini S, Coletta M, Orsini F, Giardina B, Misiti F (2005). Aß(31–35) and Aß(25–35) fragments of amyloid beta-protein induce cellular death through apoptotic signals: Role of the redox state of methionine-35. FEBS Letters., 579(13):2913-2918.
  4.  Varadarajan S, Kanski J, Aksenova M, Lauderback C, Butterfield DA (2001). Different Mechanisms of Oxidative Stress and Neurotoxicity for Alzheimers Aß(1-42) and Aß(25-35). J. Am. Chem. Soc., 123(24):5625–5631.
  5. Yan XZ, Qiao JT, Dou Y, Qiao ZD (1999). ß-amyloid peptide fragment 31–35 induces apoptosis in cultured cortical neurons. Neuroscience., 92(1):177-184.

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