Decline in hippocampal plasticity mediated by deficits in D-serine

Most naturally occuring amino acids in animals are of the L stereoisomerism, but D-serine is an amino acid that does have biological activity. It is known to activate NMDA receptors and induce NDMA receptor-dependent synaptic plasticity. And, there is evidence that deficiencies in D-serine are involved in the decline in hippocampus-dependent memory that occurs during aging.

Serine racemase is the enzyme that converts the naturally occuring L-serine to D-serine. Turpin et al looked at the mRNA and protein levels of D-serine in young and old Wistar rats as well as young and old Lou/C/Jall rats, which represent a model of aging without memory decline. D-serine levels were significantly reduced only in the hippocampus of aged Wistar rats as compared to young ones, −47.8% for mRNA levels and −25.1% for protein levels. When the researchers induced isolated NMDA receptor based field excitatory postsynaptic potentials on transverse hippocampal slices in Wistar rats, the recording was weaker in old animals than young ones. This difference between old and young was not apparent in the recordings from Lou/C/Jall rats. Crucially, when exogenous D-serine was added to the cerebrospinal fluid of Wistar rats, the age-related decrease in isolated NMDA receptor mediated synaptic potentials was rescued and there were no longer any signifcant difference between young and old rats. This strongly suggests that diminished D-serine can be responsible for lowered activity by NMDA receptors in the hippocampus.

Interestingly, the authors note that Lou/C/Jall rats have a reduced oxidative metabolism and less ROS production as compared to other strains (i.e., Wistar), don’t show any age-dependent reductions in the expression of serine racemase, and are generally a model for healthy aging without cognitive decline. Thus, the serine racemase gene may be a common and/or prototypical target of DNA-based oxidative damage in the aging brain.


Turpin FR, et al. 2009 Reduced serine racemase expression contributes to age-related deficits in hippocampal cognitive function. Neurobiology of Aging, Article in Press. doi:10.1016/j.neurobiolaging.2009.09.001.

Beta amyloid precursor promotes synaptogenesis

Amyloid precursor protein (APP) is heavily implicated in the progression of Alzheimer’s disease. When proteolytically processed they yield 40 and 42 amino acid amyloid peptides which form the beta amyloid plaques one often hears about.  APP/APLP2double knock-out mice have reduced protein expression at the neuromuscular synapse and have generally defective synapses. Wang et al have been studying this defect and have found that:

  • APP synthesized in muscle and motor neurons end up in the pre and post synaptic sites at 1:1 stoichiometry, on the basis of antibody immunoreactivity.. This indicates that its expression at both sites is necessary for the proper development of the neuromuscular synapse.
  • Postsynaptic APP deletion inhibits presynaptic vescicle release, indicating that the defects in synapse function are bidirectional.
  • At embryonic day 12.5, APP expression is low, and nerve endings are not yet in contact with muscle. But at embryonic day 14.5 when synaptogenesis begins, APP expression spikes in both neural and muscle tissue. Major defects in the APP/APLP2 double knock out mutants don’t begin until embryonic day 16.5, perhaps because interaction between proteins across the synapse is necessary for proper function.
  • After transfecting an APP expression construct into HEK293 cells with hippocampal neurons, the area of the cells covered by synaptophysin increased as compared to negative control, as did the number of synaptic puncta, both indicating that APP acts as a synaptic adhesion protein. Double knock out APP/APLP2 neurons had ~ 3 +/- 1 synaptic puncta per HEK293 cell as compared to ~ 10 +/- 1 for controls, further supporting the characterization of APP as necessary for synpatogenesis.

Downregulation of this synaptic adhesion property, which could possibly be inhibited by the beta amyloid plaques, would lead to the synaptic disfunction associated with Alzheimer’s pathogenesis. Perhaps a drug that inhibits the proteolytic enzyme that cleaves APP into amyloid peptides could act as a preventative drug for the disease for individuals with warning signs.


Wang et al. 2009 Presynaptic and postsynaptic interaction of the amyloid precursor protein promotes peripheral and central synaptogenesis. Journal of Neuroscience 29:10788-10801. doi:10.1523/JNEUROSCI.2132-09.2009.

Tau protein as cerebrospinal fluid markers in Alzheimer’s Disease

Buckhave et al have some interesting results from a longitudinal study of 119 patients with AD. At baseline, CSF levels of the microtubule-associated tau protein was significantly higher in both AD cohorts (693±301 nanograms per liter and 663±308 ng/l) than in the control group (412±232 ng/l). Additionally, baseline CSF levels of beta amyloid were lower in both AD cohorts (275±103 ng/l and 288±103 ng/l) as opposed to the baseline control group (659±179 ng/l). At a two year follow up, CSF levels of tau protein had increased in both of the AD cohorts and decreased slightly in the control group, although the divergence was only significant in one of the AD cohorts. These seem like they would both be good markers for clinical trials to test the efficacy of AD treatments.


Buchhave P, Blennow K, Zetterberg H, Stomrud E, Londos E, et al. (2009) Longitudinal Study of CSF Biomarkers in Patients with Alzheimer’s Disease. PLoS ONE 4(7): e6294. doi:10.1371/journal.pone.0006294.

Variability to apoptotic response mediated by functional protein levels

When aptosis is induced in cell populations with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), there is a surprising amount of variation in both how long it takes for cells to die and whether or not they will ever do so. For example, when exposed to 50 nanograms of TRAIL and cycloheximide, some mammary gland cells die within 2-5 hours of exposure (about 30%), some die within 5-10 hours (about 40%), some die within 10-25 hours (about 20%), and some do not die at all within the 25 hour time frame (about 10%). Spencer et al recently found that the rate at which the apoptosis promoting protein BID is truncated into its active form tBID to reach a concentration above a certain threshold level set by another set of proteins (the anti-apoptotic BCL2 protein family) is what accounts for most of this variability. Seems to me like a case of competitive enzyme inhibition. tBID then induces pore-forming proteins (BAX and BAK) to self-assemble in mitochondria, which leads to mitochondrial outer membrane permeabilization, the “point of no return” in this cell death pathway. Cool paper, suggesting that we may be able to enhance our anti-cancer approaches by some sort of genetic technique to alter the protein expression levels of the BCL2 family, and then hit the tumorous cells with the TRAIL, for a more powerful one-two punch.


Spencer SL, et al. 2009 Non-genetic origins of cell-to-cell variability in TRAIL-induced apoptosis. Nature 459: 428-432. doi:10.1038/459334a.

Chipuk JE, et al. 2006 Mitochondrial outer membrane permeabilization during apoptosis: the innocent bystander scenario. Cell Death and Differentiation 1396-1402. doi:10.1038/sj.cdd.4401963.

Bastiaens P. 2009 Systems biology: When it is time to die. Nature 459: 334-335. doi:10.1038/459334a

Genetic correlates of long age

There have been sparce tests of genome-wide associations between gene expression and longevity in humans, but more are coming up the pipeline. Kerber et al (2009) used a dataset of Utah grandmothers to test 2151 always expressed genes in a proportional hazards model. The predicted mortality from their six gene model was able to account for 23% of the variance in predicted mortality. Here are the genes in their multivariate model as well as the coefficients (which are rough indicators of how important the gene is to the model):

  • CORO1A (-0.27),
  • FXR2 (0.21),
  • CBX5 (-0.074),
  • PIK3CA (-0.0094),
  • AKAP2 (-0.0086),
  • CUL3 (-0.0081).

A very cool study and hopefully there will be more like it soon.


Kerber RA, et al. 2009 Gene Expression Profiles Associated with Aging and Mortality in Humans DOI: 10.1111/j.1474-9726.2009.0046.

Stress and culture

It is interesting to compare how measures of psychological stress differ across cultures. The Whitehall study, a longitudinal study to determine the social correlates of health, has been going since 1967. Since it evaluates civil servants with the same access to healthcare in the same general living circumstances, it has been able to control for a number of potentially confounding factors. Whitehall I found increased mortality and increased morbidity (poor health) in male subordinate workers.

Whitehall II found that workers under 50 with self-reports of high stress had a 68% increased chance to have heart attack or angina. It’s not the actual demands of the job, as the “high octane” managers and executives do not see worse health outcomes, but the perception of a lock of control in subordinate workers that is correlated with poor health outcomes. Consistent with that suggestion, men who were administrators or executive were less likely to die compared to the average, and that correlation remained steady across age cohorts. Therefore, in this British sample a sense of job control was found to be negatively correlated with the likelihood of coronary heart disease in a dose-dependent manner.

In Japan, although karoshi is a occupational hazard, the culture regarding work is somewhat different. Nomure et al (2005) found that there was actually an inverse relationship between job stress and the risk of cardiovascular disease in one Japanese sample, which is surprisingly different and suggests that perhaps people are more comfortable with a less control in the workplace. However, the mean age of their cohort was only 30, which raises some questions.

Wheatley et al (1995) gave subjects across 3 cohorts in Great Britain (GB), the US, and China a questionnaire about stress differences in daily life. People from GB said that the most stressful aspects of their lives were social habits, people from the US said that the most stressful aspect of life were sexual problems, and the Chinese reported stress to be due mainly to sleep disturbances. Overall, China was the least stressed of the three cohorts. So, different aspects of daily life were reported to be stressful across these three cultures. This has been found by other studies as well. Acadmemic stress is a more significant stressor in Korea and Japan as compared to GB (Colby, 1987). Black South Africans report less stress from uncertainty in the workplace than do White South Africans (Booysen, 2000). Since daily hassles can have a similar or even greater impact on health than major life events, these indices matter.

The fact that stress is a cultural phenomenon answers some questions, but raises many more. Is minimizing psychological stress actually the most important outcome for some cultures? There is reason for individuals to rank it highly, given that it correlates highly with health outcomes and possibly happiness as well. If so, are they able to measurably reduce it? The most intriguing possible outcomes of this research regard whether it is possible to develop strategies that allow us to minimize stress without hindering other life goals such as contributing to society and securing a good career.


Colby, BN. 1987 Well-being: A theoretical program. American Anthropologist, 89:879-895.

Fairhurst UJ,  Booysen I. 2000 Health services foster community cohesion, the case of the Northern Province, South Africa.  IGU Regional Workshop: Commission on Gender and Geography, Beyond Tolerance: Social and Spatial Coexistence – Lessons of Gendered Exclusions. Tel Aviv, Israel, 28 May – 1 June.

Effects of glucocorticoids on stress and aging

Basal glucocortcioids increase with age, and have negative feedback impairments. Healthy older human’s basal glucocortcioids levels are not different from college aged males, although they are a little bit higher during the evening. Adults with higher levels of CORT (in their daily fluctuations), have diminished hippocampal-dependent memory consolidation  (Lupien et al, 1998). There are other stress related responses that decrease in age as well. In response to infection, the response of immune system to that challenge is blunted in aged organisms as compared to younger, in humans as well as rodents. Repair mechanisms following injuring take longer to have affect in aged versus younger organisms. Following a “temperature challenge”, it takes aged animals longer to return their body temperature to baseline levels. Older rats in an animal field show less locomotion and more stress when exposed to a novel environment in an open field test.

Humans in response to survey type questions indicate a heightened level of stress when faced with novel situations. Following a stressor, physiologically it takes longer for levels of noepinephrine and epinephrine to return to baseline levels, and the responsiveness of the heart and blood vessels are somewhat diminished. If you inject tumor cells into young and old rats, tumor grow faster in old rats. However, if you inject glucocorticoids in rats in response to stressors in young rats, then the tumor rates in both age cohorts are the same. We know that glucocorticoids inhibit the immune system, so differences in glucorcoticoids may be responsible for the tumor growth differences. There is evidence that enlarged adrenal glands, peptic ulcers, and reduced HPC volume, signs of chornic stress, can lead to death at a very young age in vervet monkeys (Uno et al, 1989).

This brings up the glucocorticoid endangerment hypothesis. In the presence of glucocorticoids, neurons are believed to be more vulnerable to some other toxin or extrinsic injury, “metabolic insults”. Glucocorticoids downregulate glucose tranporter gene expression, which inhibits glucose transport, and reduces their metabolic capacity. This might mean that the neuron has a greater probability of necrosis. This action is relatively rapid, as only 24 hour exposure either in vitro or in vivo will compromise cell survival.

Low, basal levels of glucocorticoids play a facilitative role in mitochondrial oxidation. However, very high levels of glucocorticoids lead to a reduced ability for neurons to perform ATP production, which neurons do a huge amount of simply to fuel their ion channels. This is an example of the classic inverted U-shaped dose dependent response curve. The glucocorticoid interacts with an anti-apoptic protein, BCL2, in order to produce this effect, which is a little bit weird, but there is also a U-shaped dose-dependent response curve of % cell death (in vitro, using TUNEL assay) following kainic acid exposure (Du et al, 2009), such that low levels of glucocorticoids may be “neuroprotective.” Many of genes upregulated following glucocorticoid exposure in the aging hippocampus are in the astrocytes, whereas most of the genes being downregulated are in neurons. Astrocytic proliferation may play a role in deleteriously reacting with the neurons following injuries to form glial scars, and perhaps that process can be intervened with genetically.


Lupien et al 1999. S.J. Lupien, C.J. Gillin and R.L. Hauger , Working memory is more sensitive than declarative memory to the acute effects of corticosteroids: A dose-response study in humans. Behav Neurosci 113 (1999), pp. 420–430.

Uno H, Tarara R, Else JG, Suleman MA, Sapolsky RM (1989) Hippocampal damage associated with prolonged and fatal stress in primates. J Neurosci 9:1705–1711.

Du, J. et al. Dynamic regulation of mitochondrial function by glucocorticoids. Proc. Natl Acad. Sci. USA 106, 3543–3548 (2009).

Hormones and Aging, 1995. Google Books.

Predicting longevity based on early life attributes

There is a link between positive emotions and better health outcomes, possibly mitigated through effects on the cardiovascular system. An optimistic explainatory style of life events may lead to a longer life. Danner et al (2001) analyzed the early-life autobiographies of women in the nun study and correlated them with health outcomes in a longitudinal manner. On average, 1.0% increases in the number of sentences expressing positive emotions led to 1.4% decreases in the hazard function of the Cox regression model (ie, the mortality rate). Stats are hard to do here, but look at page 8 of their study because they have a sick graph showing quartile rankings versus the probability of survival.


Danner DD, et al. 2001 Positive emotions in early life and longevity: Findings from the nun study. Personality Processes and Individual Differences. DOI: 10.1037//0022-3514.80.5.804.

Describing age-related memory decline

Morrison and Hof (2007) review the mechanisms of action for memory decline in both Alzheimer’s diseases (AD) and non-AD individuals. For AD patients, the key factor seems to be neurofibrillary tangles (NFTs), which are correlated with the death of neurons in corticocortical curcuits, and which disconnect regions within the neocortex. Counter-intuitively, the most damaging changes for everyday life activities probably do not occur in the hippocampus but instead in the association neocortex. Preventing neuron death there is probably the best potential strategy to deal with the disease.

Complicating the matter is that non-AD patients still show memory loss with aging but do not have significant neuron losses in either the neocortex or the hippocampus. In the prefrontal cortex of monkeys, dendritic length and numbers of dendrite segments does not change with age, but the number of dendritic spines emerging from the base and apex of pyramidal cells is 35% less in aged monkeys as compared to young ones. This would decrease the probability of excitation in these neurons and could help account for memory decline without neuron loss. Other noted changes from young to old brains with cell death are decreased glutamate receptors in these same pyramidal neurons, changes in the NR1subunit of NMDA receptors of the dentate gyrus, altered synpatic transimisson due to decreased glutamate release in the outer and middle layers of the dentate gyrus as well as CA3, and probable differences in the way estrogen affects dendrite spine density in CA1. Stopping the structural changes would be hard and is not currently a priority but it is interesting to speculate whether it would be feasible and how it would happen.


Morrison JH, Hof PR. 2007 Life and death of neurons in the aging cerebral cortex. International Review of Neurobiology 81:41-57. doi:10.1016/S0074-7742(06)81004-4.

Hypothesizing on the mechanism behind life-extending capabilities of caloric restriction

Rodents fed 25-60% less than free-feeding controls can live up to 50% longer. This is a cross-species effect, holding true for yeast, rotifers, spiders, worms, mice, fish, and rats, and maybe non-human primates (although the longer the animal lives, the more expensive this effect is to establish). It is known to delay a number of diseases in animal models, but how? Koubava et al (2003) set out to explain the mechanism. They analyze three main models.

One is the theory that oxidative damage caused by reactive oxygen species leads to cellular degradation. If caloric restriction (CR) reduces metabolism, oxidative damage should be reduced as a simple consequence. Oxidative damage has shown to be lower in CR animals, but metabolism is not slower by most measures (although measuring this is non-trivial).

The second theory is that CR speeds up protein turnover, which delays aging because aberrant proteins and a reduction of protein turnover are tell-tale signs of aging. Perhaps it does this because when the body runs out of fat it triggers the degradation and therefore the turnover of proteins. There is some evidence for this, but the increase in protein turnover is not uniform throughout the body: some regions show it and some regions do not.

Finally, it is possible that CR leads to a decrease in protein modification by advanced glycation end products that are associated with age-related diseases. This has been demonstrated empirically, but it does not explain all of the beneficial effects of CR and therefore is unlikely to be the primary mechanism.

The authors review the evidence and present their own combinatorial model that relies on hormone regulation. This is a controversial yet potentially enlightening topic for neuroscientists.


Koubova J, Guarente L. 2003 How does caloric restriction work. Genes and Development 17:313-321. doi: