24 May 2019

Does neurogenesis keep the brain sharp? This unsettled debate is getting new fuel this week. In the May 23 Cell Stem Cell online, researchers led by Orly Lazarov at the University of Illinois, Chicago, report that they can find newborn neurons in the postmortem brains of people who died in their 80s and 90s. However, the number of these cells dropped steeply in those who’d had mild cognitive impairment or Alzheimer’s disease. Notably, greater numbers of newborn neurons correlated with better scores on a cognitive battery, as well as with more preserved synaptic function. Though small, the study hints at a link between neurogenesis and cognition, Lazarov said.

“This is an important paper, because it adds to the growing evidence that adult neurogenesis might be affected in Alzheimer’s disease,” noted Gerd Kempermann at the Center for Regenerative Therapies in Dresden, Germany. For her part, Lazarov believes the connection could have therapeutic potential. “If we find a way to enhance neurogenesis early, we might be able to preserve hippocampal plasticity and delay cognitive decline,” she told Alzforum.

It’s widely accepted that people can stimulate neurogenesis by way of regular exercise. But how does that work, and can science find molecular drug targets? In the May 23 Stem Cell Reports online, researchers led by Davide De Pietri Tonelli at the Italian Institute of Technology in Genoa identified a microRNA, miR-135a, that mediates the effect of exercise on neurogenesis. Overexpressing miR-135a in active mice suppressed neurogenesis and negated the effects of running on a wheel, while inhibiting miR-135a in sedentary mice pumped up neurogenesis, mimicking an active lifestyle. Further study of exactly how miR-135a affects cells could help identify pharmacologic targets, the authors suggested.

Proliferation Brake. Dividing neural progenitor cells (pink) in culture (left) are stimulated by an inhibitor of miR-135a (center) and suppressed by its overexpression (right). [Courtesy of Pons-Espinal et al., Stem Cell Reports.]

The new finding comes on the heels of a report from Spain that neurogenesis persists quite robustly in old people but plummets when Alzheimer’s takes hold. That study compared the numbers of new neurons across Braak stages in the brains of 13 healthy controls who had died between the ages of 43 and 87, and 45 AD patients who died between ages 52 and 97 (Mar 2019 news). 

Lazarov focused on old brains and correlated neurogenesis with cognitive status, not neuropathology. First author Matthew Tobin analyzed hippocampi from 18 participants in the Rush Memory and Aging Study who had died between 79 and 99 years old. Six of them had been cognitively normal, six had had MCI, and six AD dementia. Four of the six MCI cases had AD pathology. Tobin and colleagues took dentate gyrus sections, immunostained them for markers of neural progenitor cells (NPCs) and newborn neurons, then used MRI volumetric data on the same participants to estimate neurogenesis in the whole dentate gyrus.

Tobin saw proliferating NPCs and newborn neurons in all samples. On average, a cubic millimeter of brain section contained 800 newborn neurons. However, this number varied widely from person to person, with some having almost none and others as many as 3,000 per cubic millimeter, Lazarov told Alzforum. The overall numbers are much lower than those in the Spanish study, which reported an average of 25,000 newborn neurons per square millimeter in healthy aged brain. This discrepancy may be due to methodological differences. The Spanish group developed a tissue processing protocol that they say enhances staining for doublecortin (DCX), the gold-standard marker for newborn neurons.

For their analysis, Lazarov and colleagues focused on neuroblasts, cells that have committed to a neuronal fate but are still dividing. These cells expressed both DCX and proliferating cell nuclear antigen (PCNA), a marker of dividing cells. Importantly, the number of these proliferating neuroblasts correlated with cognitive status, dropping by about half in MCI and AD. The more proliferating neuroblasts a person had in his or her dentate gyrus, the higher the scores on a battery of 19 cognitive tests. In addition, higher numbers of proliferating neuroblasts associated with better synaptic function, as measured by ELISAs that quantified complexes of synaptic SNARE proteins. Previous research had linked the interaction of these synaptic proteins to better cognition and lower risk of AD (Honer et al., 2012; Ramos-Miguel et al., 2018). 

Curiously, the authors found no correlation between neurogenesis and the amount of plaques or tangles in the brain, at odds with the Spanish study, which reported fewer newborn neurons at higher Braak stages. Her finding might reflect cognitive reserve, Lazarov said. For example, she included seven brains at Braak stage 4; two of these people had died with normal cognition, three with MCI, and two AD. Neurogenesis in these brains varied, correlating with cognitive status rather than pathology. This could mean that a higher rate of neurogenesis helps a person withstand the effects of plaques and tangles, Lazarov said. “It’s very important to keep studying large cohorts in order to understand what additional lifestyle factors and co-morbidities might affect neurogenesis,” she told Alzforum.

One such factor is physical exercise. Numerous studies have found it stimulates neurogenesis (e.g. May 2002 news; May 2002 news; Mar 2005 news). Because exercise also changes microRNA expression, De Pietri Tonelli and colleagues wondered if these regulatory transcripts might connect sport and neurogenesis (Bao et al., 2014; Cosín-Tomás et al., 2014; Hu et al., 2015). Joint first authors Meritxell Pons-Espinal and Caterina Gasperini isolated NPCs from the dentate gyri of mice that had spent the previous 10 days periodically running on a wheel, or lazing around their cages. In three separate experiments on 16 mice each, the researchers identified three microRNAs that were consistently suppressed by running.

The authors transfected each of the microRNAs into cultured mouse NPCs, and found that only miR-135a suppressed their proliferation. Blocking miR-135a in NPCs by adding an RNA of complementary sequence triggered cell division (see image above). The same pattern held true in vivo, where suppressing miR-135a in indolent mice boosted their NPC proliferation as much as running did. Conversely, overexpression of miR-135a suppressed neurogenesis in running mice down to the levels seen in sedentary ones.

How about aging? The researchers inhibited miR-135a in 21-month-old sedentary mice. This boosted their neurogenesis about sixfold over that of aged-matched controls, and twofold compared to sedentary young mice.

To glean clues as to what miR-135a might regulate, the scientists analyzed proteome changes in cultured mouse NPCs. They found 17 proteins whose concentration was consistently lower when miR-135a was overexpressed, and up when miR-135a was inhibited.

Many of these proteins function in a phosphatidylinositol signaling system. Possibly, this signaling pathway promotes proliferation, and might represent a therapeutic target, the authors suggested. Supporting this, previous research found that PI3K-Akt signaling mediated the effect of exercise on neurogenesis and synaptic plasticity (Chen and Russo-Neustadt, 2005; Bruel-Jungerman et al., 2009). 

Henriette van Praag at Florida Atlantic University in Boca Raton called the findings striking. “The identification of a molecular mechanism underlying running-induced hippocampal cell proliferation advances our understanding,” she wrote to Alzforum. Van Praag suggested that future mouse studies test whether inhibiting miR-135a also enhances learning and memory. In human studies, researchers could look for correlations between microRNA levels, lifetime exercise, and neurogenesis. —Madolyn Bowman Rogers

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References

News Citations

1. Neurogenesis Tapers In Older Brains, But Plummets in Alzheimer’s 25 Mar 2019
2. Keep It Up: Activity-Induced Neurogenesis in Hippocampus Not Just a Blip 22 Nov 2002
3. Run For Your Brain: Exercise Boosts Hippocampal Gene Expression, Neurogenesis 22 Nov 2002
4. Sorrento: More Fun, Less Amyloid for Transgenic Mice 18 Mar 2005

Paper Citations

1. Honer WG, Barr AM, Sawada K, Thornton AE, Morris MC, Leurgans SE, Schneider JA, Bennett DA. Cognitive reserve, presynaptic proteins and dementia in the elderly. Transl Psychiatry. 2012;2:e114. PubMed.
2. Ramos-Miguel A, Jones AA, Sawada K, Barr AM, Bayer TA, Falkai P, Leurgans SE, Schneider JA, Bennett DA, Honer WG. Frontotemporal dysregulation of the SNARE protein interactome is associated with faster cognitive decline in old age. Neurobiol Dis. 2018 Jun;114:31-44. Epub 2018 Feb 26 PubMed.
3. Bao TH, Miao W, Han JH, Yin M, Yan Y, Wang WW, Zhu YH. Spontaneous Running Wheel Improves Cognitive Functions of Mouse Associated with miRNA Expressional Alteration in Hippocampus Following Traumatic Brain Injury. J Mol Neurosci. 2014 Dec;54(4):622-9. Epub 2014 Jun 12 PubMed.
4. Cosín-Tomás M, Alvarez-López MJ, Sanchez-Roige S, Lalanza JF, Bayod S, Sanfeliu C, Pallàs M, Escorihuela RM, Kaliman P. Epigenetic alterations in hippocampus of SAMP8 senescent mice and modulation by voluntary physical exercise. Front Aging Neurosci. 2014;6:51. Epub 2014 Mar 20 PubMed.
5. Hu T, Zhou FJ, Chang YF, Li YS, Liu GC, Hong Y, Chen HL, Xiyang YB, Bao TH. miR21 is Associated with the Cognitive Improvement Following Voluntary Running Wheel Exercise in TBI Mice. J Mol Neurosci. 2015 Sep;57(1):114-22. Epub 2015 May 28 PubMed.
6. Chen MJ, Russo-Neustadt AA. Exercise activates the phosphatidylinositol 3-kinase pathway. Brain Res Mol Brain Res. 2005 Apr 27;135(1-2):181-93. Epub 2005 Jan 26 PubMed.
7. Bruel-Jungerman E, Veyrac A, Dufour F, Horwood J, Laroche S, Davis S. Inhibition of PI3K-Akt signaling blocks exercise-mediated enhancement of adult neurogenesis and synaptic plasticity in the dentate gyrus. PLoS One. 2009 Nov 19;4(11):e7901. PubMed.

Further Reading

News

1. Newborn Neurons Abundant in Adult Human Hippocampus 7 Jun 2013
2. Fresh Neurons Seed the Human Striatum Throughout Life 21 Feb 2014
3. Taos: New Neurons in New Mexico—Highlights from Keystone 17 Feb 2011
4. Watching Adult Neurogenesis—In Primates It Takes Time 11 Jun 2011
5. Early Casualty, Neurogenesis Cripples Cognition in AD Mice 19 Mar 2010
6. Exercise Pill? Pharmacological Mimics Boost Cognition in Lazy Mice 9 Sep 2018