Adrenomedullin is Involved in Age-Related Memory Loss

Researchers have identified adrenomedullin as a contributing factor in age-related memory loss in mice, and in the open access paper here note that levels of adrenomedullin increase with age in humans as well. This research is a fair distance from a rigorous proof of the relevance of adrenomedullin to human memory loss, but it is nonetheless quite interesting. The observed correlations suggest that the important connection is between adrenomedullin and the aggregated tau protein that gives rise to tauopathies, and consequently that tau is influential in the lesser degree of mental decline with age that occurs in people without full-blown neurodegenerative conditions. Aggregation of altered tau protein is a fairly fundamental form of age-related damage, something that occurs as a side-effect of the normal operation of metabolism, so it might be expected to contribute to declining function in proportion to its presence.

Memory loss is a common characteristic of normal aging, and is greatly accelerated in some neurodegenerative diseases. The causes of memory loss during normal aging are not completely understood. Atrophy of some brain areas has been shown in normal aging and changes in intrinsic neural electrical excitability associated with oxidative stress have been hypothesized as potential causes. Subtle perturbations in stabilization of neuronal cytoskeleton, reminiscent of those occurring during Alzheimer's disease (AD) neurodegeneration, may also be an important underlying cause of age-associated neuronal dysfunction and cognitive decline. In this line, modifications of tau expression and status akin to those of tauopathies are also typical of normal aging and their distribution pattern correlates with memory capabilities.

In the search for predictive blood biomarkers of AD cognitive decline, some studies have found that mid-regional proadrenomedullin is elevated in the plasma of AD patients and that the concentration of this peptide could have predictive value in the progression from predementia to clinical AD, although a recent study found no correlation. The proadrenomedullin gene, adm, generates two biologically active peptides: proadrenomedullin N-terminal 20 peptide (PAMP) and adrenomedullin (AM).

Expression of these peptides is widespread and several functions have been ascribed to them, including vasodilatation, bronchodilatation, angiogenesis, hormone secretion regulation, growth modulation and antimicrobial activities, among others. In the central nervous system (CNS), AM is expressed throughout the whole brain and spinal cord where it acts as a neuromodulator. It has been shown that plasma levels of AM increase with normal aging.

Knockout studies have shown that total abrogation of adm results in embryo lethality. To circumvent this problem, we generated a conditional knockout model where adm was eliminated just from neurons. Consequently, we have shown that aged mice that lack neuronal AM have better contextual and recognition memory than their wild type littermates. In parallel, the brain cortex and hippocampus of these mice have a lower accumulation of phosphorylated tau, suggesting that tau may be the link between lack of AM and memory preservation, although we cannot rule out other alternative molecular pathways. In addition, we also showed that older human individuals present higher levels of AM and lower levels of acetylated tubulin in their brains than younger controls.

Our data suggest that reducing AM/PAMP levels may constitute a novel path to preventing or delaying memory loss. A few years ago, a particular single nucleotide polymorphism (SNP) close to the adm gene was found to be responsible for a natural reduction in the circulating levels of AM and to correlate with cancer susceptibility. Therefore, it would be interesting to test whether carriers of this SNP are more protected from developing memory impairment. Also, several physiological inhibitors of AM have been proposed for clinical development, and some of these inhibitors may be used for the pharmacological prevention of age-related memory loss.



This genetics-related memory loss problem sounds similar to what happens in the BDNF gene where there is a risk of depression and faster decline in AD patients who have the BDNF SNP rs6265 A allele. About 40% of Caucasians are either Homozygous or heterozygous for the A allele and have these and other memory or mental disease risks. On another cognitive topic, I have begun to think that humans have a discernment gene whereby about 10% of the population is homozygous for the good gene allele (scientists and STEM people among others), about 30-40 percent are heterozygous for the discernment gene allele. and 40-50% have a deficient discernment allele, in that they have little or no ability to discern truth from untruth. We really should start to figure out some of these mental and memory puzzles that plague the human race.

Posted by: Biotechy at December 5th, 2017 4:20 PM
Comment Submission

Post a comment; thoughtful, considered opinions are valued. New comments can be edited for a few minutes following submission. Comments incorporating ad hominem attacks, advertising, and other forms of inappropriate behavior are likely to be deleted.

Note that there is a comment feed for those who like to keep up with conversations.