Archive for the ‘Aging’ Category

In their review of the “neuroproteome” associated with aging and cognitive decline, VanGuilder and Freeman discuss some of the technical approaches and findings in the field.

This illustrative figure shows some of the major cellular players involved and lists some example proteins involved in four important pathways:

"numerous cell types (microglia (green), astrocytes (orange), oligodendrocytes (blue), and neurons (violet)) and subcellular components (mitochondria (brown), endoplasmic reticulum (green), cytoskeleton (orange/red), and synaptic machinery) are affected by brain aging"; doi: 10.3389/fnagi.2011.00008

As you can see, many proteins have been implicated, although the degree of up-/down-regulation of these proteins is not fully elucidated.

The authors mention the value of standardizing efforts to profile the proteome in important brain regions across the lifespan of rodent models. This step would make these results more robustly quantitative and help iterate towards a consensus.


VanGuilder H. D. and Freeman W. M (2011) The hippocampal neuroproteome with aging and cognitive decline: past progress and future directions. Front. Ag. Neurosci. 3:8. doi: 10.3389/fnagi.2011.00008

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More neurons are born than necessary, and synaptic pruning is the process by which neurons that have not made as many functional synaptic connections with other neurons are preferentially degraded.

Abitz et al counted cells in the medial thalamus of newborn and adult brains using a optical fractionator and Giemsa staining which binds to phosphate groups of DNA. They distinguished small neurons from glial cells on the basis of chromatin pattern, the size / shape of the nucleus, and the visibility of the nucleolus. Here’s an example of the Giemsa stained  cells via micrographs:

scale bar = 10 micrometers, doi:10.1093/cercor/bhl163

They found an average of 11.2 million neurons in the newborn MD thalamus, which decreased to an average of 6.43 million neurons in adults, probably as a result of synaptic pruning. On the other hand, they found 36.3 million glial cells in adults, much higher than the 10.6 million they found in newborns, suggesting that glial progenitor cells still have a few proliferation cycles to undergo in development.

Elsewhere, Elston et al measured the number of spines in the average pyramidal cell of macaque brains in the primary visual cortex (V1), the inferior temporal gyrus (TE), and the prefrontal cortex (PFC) at different stages of development. They found an inverted U shaped curve of spine number with log age:


The authors conclude that “synaptic activity thresholds that reinforce synapses and stabilize dendritic spines may vary across cortex.” It is interesting that the regions follow the same general trend in each region, peaking at 3.5 months.


Maja Abitz , Rune Damgaard Nielsen , Edward G. Jones , Henning Laursen , Niels Graem , and Bente Pakkenberg. Excess of Neurons in the Human Newborn Mediodorsal Thalamus Compared with That of the Adult. Cerebral Cortex Advance Access published on January 11, 2007, DOI 10.1093/cercor/bhl163.

Guy N. Elston, Tomofumi Oga, and Ichiro Fujita. Spinogenesis and Pruning Scales across Functional Hierarchies.  J. Neurosci. 29: 3271-3275; doi:10.1523/JNEUROSCI.5216-08.2009

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Scholz et al performed diffusion tensor imaging on 48 adults randomly placed in either a juggling or control group. By the end of the 6-week training each of the adults in the juggling group could perform 2 cycles of the 3 ball cascade, which is somewhat but not overly impressive. As compared to their pre-scanning fractional anisotropy, a somewhat loose measure of myelination, fiber density, and axon diameter, the juggling group had a percent increase of ~ 5.5 +/- 1.5 % immediately following the training, and a percent increase of ~ 4 +/- 1 % four weeks later. The control group had no real increase following training, which makes sense because they didn’t do anything!

The increase four weeks post-training indicates that although the effects of the training diminish somewhat over time, they should last for at least a little while. Perhaps further studies could continue to perform diffusion tensor imaging on the adults to see when the percent increases due to training are extinguished, if ever. A back of the envelope calculation based on a linear trend would suggest that after ~ 15 weeks following training the increased would be gone. But the reality may be wildly different.


Scholz J et al. 2009 Training induces changes in white-matter architecture. Nature Neuroscience 12 1370-1371. doi:10.1038/nn.2412

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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.

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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.

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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.

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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

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