Alzheimer's & Senile Dementia

Carnosine may prevent proteasomal decline in Alzheimer's disease

The body accumulates a lot of sludge, and we need an efficient sludge removal system. When protein “sludge” accumulates, the gears of the cell cycle can get clogged up. The function of the brain, like many other vital organs, depends upon the timely disposal of abnormal or damaged proteins. Proteasome is our main "cleaning lady" in the cells. Once the proteasome becomes inhibited, ubiquitinated, misfolded, aggregated, and oxidized proteins accumulate in the cells and lead to neurodegeneration and cell death.

What is the proteasome?

The proteasome is the main proteolytic enzyme, a large ~700-kDa complex, composed of 28 individual - and ß-subunits, which are arranged in four rings, with each ring composed of either seven - or seven ß-subunits. parts.

The proteasome is a multicatalytic protease and the principal non-lysosomal proteolytic system in all eukaryotic cells. It plays a central role in virtually all regulatory pathways as for instance cell-cycle regulation, differentiation, and apoptosis (programmed cell death).

The proteasome modulates the intracellular concentrations of presenilins 1 and 2 (Baki et al., 2001). These two proteins, when mutated, appear responsible for most of early onset forms of Alzheimer's disease and this is thought to be due to the exacerbation of the pathogenic pathway of the maturation of the beta-amyloid precursor protein. Controlling presenilins concentrations could have drastic repercussions on cell physiology as suggested by the fact that proteasome inhibitors drastically potentiate the 'normal' or 'pathogenic' presenilins phenotype related with betaAPP processing. Proteasome activity is impaired in the Alzheimers´s disease (AD) brain. Proteasome protectors, like carnosine, are a potential target for therapeutic intervention in AD.

How does the proteasome work in the cells?

In normal cells, the proteasome ensures the elimination of numerous proteins that play critical roles in cell functions throughout the cell cycle. Defects in the activity of this proteolytic machinery can lead to the disorders of cell function that is believed to be the root cause of certain diseases. Indeed, many proteins involved in the control of cell cycle transitions are readily destroyed by the proteasome once their tasks have been accomplished.

The proteasome removes proteins that have been tagged for degradation by a peptide called ubiquitin. Through its role in protein disposal, the proteasome-ubiquitin pathway helps regulate many basic cellular processes including the cell cycle and cell division, cell differentiation, cellular signaling, cellular metabolism and DNA repair. Thus a malfunctioning proteasomal system has far-reaching consequences.

As cells age, after many cell divisions, proteasome activity declines. At the same time, more and more proteins undergo damage through a process called carbonylation and reactive carbonyl derivatives (RCD) are formed in the cells. The age-related changes of the RCD appear to be associated with proteasome activity that decreases with age.Thus the proteolytic system becomes increasingly inadequate to deal with the increasing numbers of abnormal or unneeded proteins, which can irreversibly form cross-links and turn cellular processes awry.

When the proteasome is inhibited, oxidized and aggregated proteins accumulate, and neurons degenerate and die as it happens in Parkinson´s and Alzheimer´s diseases. Carnosine both protects proteins from carbonylation and helps reverse proteasomal decline.

Carbonylated proteins inhibit proteasomal activity and this could interfere with cell cycle progression and control. A bottleneck in protein removal could shift the balance toward the accumulation of ß-amyloid deposits characteristic of Alzheimer's disease.

Proteasomal activity declines in Alzheimer´s

Researcher at the University of Kentucky provided the first direct evidence of reduced proteasome activity in Alzheimer´s disease (Keller et al., 2000). The scientists compared proteasome activity in five brain regions of normal and Alzheimer's brains, using specimens removed during autopsies. They found the activity of the proteasome significantly reduced in three brain regions showing severe degeneration in Alzheimer's disease. By contrast, proteasome activity was not reduced in two brain regions showing less or no degenerative change in Alzheimer's disease.

Another research team from France suggests a mechanism by which proteasomal impairment could in turn increase production of the amyloid-beta material that makes up senile plaques. Proteins called presenilins influence the production of amyloid-beta from its “parent” protein called amyloid precursor protein, or APP. Mutations in the presenilin genes that lead to early onset Alzheimer's disease upset the balance between production of amyloid-beta and of a neuroprotective derivative of APP called secreted APP. These mutations especially favor production of a long form of amyloid-beta that more readily collects into aggregates and eventually plaques. There is considerable evidence that presenilin protein concentrations are regulated by the proteasome.

The French research shows that inhibition of the proteasome increases production of the long aggregable form of ß-amyloid which in turn inhibits the proteasome. A vicious circle will result. The researchers propose that proteasome activators could reverse this imbalance, potentially in sporadic as well as genetic forms of Alzheimer's disease.

The neuroprotective role of carnosine

Cellular aging is often associated with an increase in protein carbonyl groups arising from oxidation- and glycation-related phenomena and suppressed proteasome activity. These "aged" polypeptides may either be degraded by 20S proteasomes or cross-link to form structures intractable to proteolysis and inhibitory to proteasome activity. Carnosine has been shown to fight most of the biochemical processes which lead to declined proteasome activity (Hippkiss 200b; Hipkiss et al., 2001, 2002). Therefore carnosine appears to be a promising dietary supplement for decreasing the risk of neurodegeneration and slowing down the initiated process.

• More on carnosine

References

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