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Keywords:

  • age;
  • hippocampus;
  • human;
  • neurogenesis;
  • transforming growth factor-β1;
  • subventricular zone

Abstract

  1. Top of page
  2. Abstract
  3. Materials and methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References

J. Neurochem. (2010) 115, 956–964.

Abstract

Neurogenesis, the birth of new neurons, continues throughout adulthood in the human subventricular zone (SVZ) and hippocampus. It is not known how levels of putative proliferation-regulating factors change with age in human adult neurogenic areas. The current project employed ELISAs to investigate changes in levels of putative proliferation-regulating factors in the healthy human SVZ and dentate gyrus throughout the adult lifespan (18–104 years). Levels of brain-derived neurotrophic factor, basic fibroblast growth factor and interleukin (IL)-1β were significantly higher in the hippocampus than in the SVZ and levels of glial-derived neurotrophic factor and transforming growth factor-α were significantly higher in the SVZ (p < 0.005), suggesting that factors with predominant influences on neurogenesis differ between the two human adult neurogenic areas. Hippocampal levels of transforming growth factor-β1 strongly increased with age (n = 9, p < 0.01), whereas hippocampal and SVZ levels of brain-derived neurotrophic factor, epidermal growth factor, basic fibroblast growth factor, glial-derived neurotrophic factor, heparin-binding epidermal growth factor, insulin-like growth factor-1, IL-1β, IL-6 and transforming growth factor-α did not change significantly with age in the SVZ or hippocampus. These findings suggest regulation of the adult neurogenic environment in the human brain may differ over time from that in other species.

Abbreviations used
BDNF

brain-derived neurotrophic factor

DG

dentate gyrus

EGF

epidermal growth factor

FGF2

basic fibroblast growth factor

GDNF

glial-derived neurotrophic factor

HB-EGF

heparin-binding EGF

IGF-1

insulin-like growth factor-1

IL

interleukin

SVZ

subventricular zone

TGF

transforming growth factor

Aging is a major risk factor for the development of a number of common central nervous system diseases such as Alzheimer’s disease, Parkinson’s disease and other neurodegenerative disorders. Even in non-diseased individuals, a decline in memory and olfactory performance is seen with aging (Robertson-Tchabo and Arenberg 1976; Doty et al. 1984; Moore et al. 1984). From recent trends showing an increase in life expectancy, it has been projected that by 2050 the proportion of the world’s population over 65 years will more than double (United Nations Department of Economic and Social Affairs 2002), suggesting that in the future the number of people affected by age-related cognitive decline and neurodegenerative disorders will greatly increase.

Neurogenesis, the birth and development of new neurons, continues into adulthood in the human brain in two regions – the hippocampal dentate gyrus (DG) and the subventricular zone (SVZ) in the lateral wall of the lateral ventricle (Eriksson et al. 1998). Neuroblasts generated in the SVZ migrate to the olfactory bulb where they become interneurons (Weickert et al. 2000; Enwere et al. 2004; Gould 2007) whereas in the DG, precursors from the subgranular zone differentiate into granule cells (Kaplan and Hinds 1977; Kuhn et al. 1996). The function of adult neurogenesis is largely unknown but experimental perturbations of adult neurogenesis suggest a role for this process in the regulation of addiction, anxiety, hippocampal-dependent memory and fine olfactory discrimination (Imayoshi et al. 2008; Kempermann 2008; Nissant et al. 2009; Revest et al. 2009; Noonan et al. 2010). Additionally, perturbations of neurogenesis occur in neurodegenerative disease, for example an increase in SVZ neurogenesis occurs in Huntington’s disease and decreased neurogenesis has been reported in Parkinson’s disease (Hoglinger et al. 2004; Curtis et al. 2007a).

Studies across a number of non-human species suggest that there is an age-related decrease in newly generated adult neurons in the DG and SVZ (Kuhn et al. 1996; Kempermann et al. 1998; Jin et al. 2003; Maslov et al. 2004; Leuner et al. 2007; Pekcec et al. 2008), for example in the marmoset brain the number of proliferating marmoset DG cells decreases by approximately 50% between the ages of 2 and 7 years (Leuner et al. 2007). This decrease is linked to an age-related decline in memory and fine olfactory discrimination in normal aging animals (Enwere et al. 2004; Drapeau and Abrous 2008). It is unknown if neurogenesis decreases with age in the healthy human brain, or if age-related functional changes in the human result from changes in neurogenesis.

Regulation of neurogenesis in the adult mammalian brain appears to depend upon levels of a number of neurogenesis- or proliferation-regulating factors. Trophic factors such as basic fibroblast growth factor (FGF2), heparin-binding epidermal growth factor (HB-EGF), transforming growth factor (TGF)-α and EGF have been shown to positively regulate proliferation in the adult murine SVZ (Tropepe et al. 1997; Jin et al. 2003; Dictus et al. 2007). Similarly, insulin-like growth factor-1 (IGF-1), glial-derived neurotrophic factor (GDNF) and FGF2 have been shown to increase proliferation in the adult murine DG (Aberg et al. 2000; Chen et al. 2005; Dictus et al. 2007). Conversely, factors such as p16INK4a, interleukin (IL)-6 and TGF-β1 negatively regulate adult murine SVZ proliferation and interleukin-1β and TGF-β1 negatively regulate adult neurogenesis in the murine DG (Wachs et al. 2006; Koo and Duman 2008; Nishino et al. 2008; Bauer 2009). Protein levels of the pro-proliferative factor TGF-α are decreased in the aged murine SVZ, whereas mRNA levels of the anti-proliferative p16INK4a are increased (Enwere et al. 2004; Nishino et al. 2008). Similarly, levels of the pro-proliferative factors FGF2, IGF-1 and GDNF are decreased in the aged murine hippocampus, whereas levels of the anti-proliferative factors IL-1β and TGF-β1 increase with age in the murine hippocampus, in effect forming an environment suggested to be conducive to cellular senescence (Nichols 1999; Casolini et al. 2002; Miyazaki et al. 2003; Shetty et al. 2005).

To date, the only study examining protein levels of proliferation-regulating factors in the human brain reported no change in hippocampal GDNF levels with age (Michel et al. 2008). Thus, it is unknown if levels of factors that regulate proliferation in neurogenic regions of the human brain change with age. Given that differences between human and non-human neurogenesis have been reported (Quinones-Hinojosa et al. 2006; Curtis et al. 2007b), that humans display a decrease in memory and olfactory performance with age (Perlmutter et al. 1981; Kaneda et al. 2000), and that stem cell-related therapies such as stimulation of endogenous neurogenesis and implantation of stem cells have been proposed as methods to treat neurodegenerative diseases (Curtis et al. 2007a), it is important to investigate whether human neurogenic regions contain similar proliferation-regulating factors as other species and whether levels of these factors change with age. This report describes a cross-sectional study of putative pro- and anti-proliferative factor levels across the whole adult lifespan in the healthy human hippocampus and SVZ.

Materials and methods

  1. Top of page
  2. Abstract
  3. Materials and methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References

Tissue collection and processing

All work involving human tissue was approved by the University of NSW Human Research Ethics Advisory Panel and conforms to The Code of Ethics of the World Medical Association (Declaration of Helsinki). Nineteen human brains of ages distributed throughout the adult lifespan (18–104 years) were collected, with consent from the next-of-kin, by the NSW Tissue Resource Centre and the Sydney Brain Bank (Table 1). Assessment of medical histories revealed no clinical signs or symptoms of neurological or psychiatric disorders, and no neuropathological abnormalities were present in the brains. After washing in 0.9% saline, one hemisphere of each brain was cut into coronal hemi-slices (0.5–1 cm thickness) and these were stored at −80°C. As the width of the SVZ varies along its dorsal to ventral aspect (Quinones-Hinojosa et al. 2006), and its boundaries can only be identified following immunohistochemistry, the dorsal to ventral aspect of the lateral wall of the lateral ventricle was dissected to a depth of 3 mm from the coronal block anterior to the block containing the anterior commissure. This tissue will subsequently be referred to as ‘SVZ’. The head of the hippocampus, containing the CA regions and DG, was dissected from the block anteriorly second to the coronal block containing the lateral geniculate nucleus. The hippocampus was not available from nine cases (see Table 1). Dissected tissue was stored at −80°C. Each SVZ or hippocampal head was homogenized in a buffer containing 100 mM 1,4-piperazinediethanesulfonic acid disodium salt, 500 mM sodium chloride, 2 mM EDTA disodium salt, 10 μM leupeptin, 0.3 μM aprotinin, 1 μM pepstatin and 0.2% Triton X-100 (pH 7), as used by Szapacs et al. (2004). All chemicals were purchased from Sigma-Aldrich (St Louis, MO, USA), unless otherwise stated. Homogenates were centrifuged at 14 000 g for 30 min at 4°C and then supernatant and pellet were separated and stored at −80°C prior to analysis.

Table 1.   Demographic characteristics of cases
Age (years)GenderPost-mortem interval (h)pHStorage time (months)Cause of death
  1. aHippocampal tissue not available from these cases.

18Male28.56.7011Unknown
21Female39.56.8330Primary cardiac arrhythmia
24aMale436.2731Idiopathic cardiac arrhythmia
46Male296.1237Acute myocardial infarction
49aFemale156.9336Arrhythmogenic right ventricular dysplasia
50aMale306.3715Coronary artery disease
59Male436.6919Atherosclerotic cardiovascular disease
64aMale9.56.9434Ischaemic heart disease
66aMale236.7423Ischaemic and hypertensive heart disease
69aMale13.56.7445Myocardial infarction due to ischaemia heart disease
69aMale196.3431Cardiac tamponade, acute myocardial infarction
73aMale486.8035Dilated cardiomyopathy, ischaemic heart disease
75Male50.56.7127Haemopericardium
78Female456.0526Multiple drug toxicity
79aMale86.6518Pulmonary embolism
85Male96.5729Severe cachexia, malignant colorectal cancer
86Male156.9433Sepsis, bilateral pneumonia, acute renal failure
98Female66.7034Pneumonia, congestive cardiac failure
104Male275.8936Bilateral bronchopneumonia

ELISA

Tissue levels of putative proliferation-regulating factors in the supernatant of homogenates were quantified by ELISA according to the manufacturer’s protocol and samples were assayed in triplicate. Optimal antibody concentrations and minimum reliable detection thresholds were determined in preliminary experiments (Table 2). Acidification of supernatant and pellet can increase detection of some neurogenic factors (Okragly and Haak-Frendscho 1997; Cunningham et al. 2002). Preliminary experiments found GDNF, IGF-1 and TGF-β1 yields were increased by a 10 min pre-treatment of the supernatant and pellet with an equivolume amount of 10 M urea (Amresco, Solon, OH, USA) in 2.5 M acetic acid followed by neutralization with 1 M HEPES in 2.7 M NaOH, thus this pre-treatment was used prior to ELISAs for these factors. This pre-treatment did not affect protein yield for any other factor and thus was omitted from the protocol for these factors.

Table 2.   Optimal ELISA kit antibody concentrations and corresponding minimum reliable detection levels established in preliminary experiments. ‘Minimum reliable detection level’ was defined as the lowest concentration of factor producing absorbance values significantly higher than the absorbance of the blanks over independent trials
FactorKit manufacturer[Coating antibody] (μg/mL)[Detection antibody] (ng/mL)Minimum reliable detection level (pg/mL)
BDNFPromega (Madison, WI, USA)UnavailableUnavailable3.90
EGFR&D Systems (Minneapolis, MN, USA)8 503.90
FGF2R&D Systems325015.63
GDNFR&D Systems220015.63
HB-EGFR&D Systems0.81003.90
IGF-1R&D Systems8 8031.25
IL-1βR&D Systems23001.95
IL-6R&D Systems82004.60
p16INK4aMTM laboratories (Heidelberg, Germany)UnavailableUnavailable7.56
TGF-αR&D Systems0.83001.95
TGF-βR&D Systems66007.80

Total protein levels were measured with a bicinchoninic acid assay (Thermo Scientific, Rockford, IL, USA) and proliferation-regulating factor levels were normalized to total protein content. For data analysis, levels of any cases that did not register above the minimum detection level were recorded as zero. Exact Wilcoxon matched-pairs tests were used to compare median levels of SVZ proliferation-regulating factors with median levels of hippocampal factors within the same cases. Significance was set at p < 0.005 after Bonferroni correction for 10 comparisons. The ability of age to predict levels of each of the proliferation-regulating factors, when controlling for pH, post-mortem interval and storage time, was established using multiple stepwise linear regression analyses, with p < 0.05 set as significant. Gender effects on factor levels were examined with Kolmogorov–Smirnov two-sample tests. All statistical analyses were performed using SPSS Statistics 17.0 (SPSS Inc., Chicago, IL, USA).

Results

  1. Top of page
  2. Abstract
  3. Materials and methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References

Regional variance in proliferation-regulating factor levels

Median levels of brain-derived neurotrophic factor (BDNF), FGF2 and IL-1β were significantly higher in the hippocampus than the SVZ (p < 0.005; hippocampal n = 11, SVZ n = 19; Fig. 1a–c). In contrast, median levels of GDNF and TGF-α were significantly higher in the SVZ compared with the hippocampus (p < 0.005, hippocampal n = 11, SVZ n = 19; Fig. 1d–e). Similarly, median levels of IGF-1 in the SVZ were higher than in the hippocampus (hippocampal n = 10, SVZ n = 19; Fig. 1f), although statistical differences could not be tested for using the Wilcoxon-matched pairs test as hippocampal IGF-1 values were below minimum detection level and hence had no variance. Levels of IL-6, EGF, HB-EGF and TGF-β1 did not differ between the SVZ and hippocampus (p > 0.005; Table 3).

image

Figure 1.  Levels of (a) BDNF, (b) FGF2, (c) IL-1β, (d) GDNF, (e) TGF-α and (f) IGF-1 showed regional differences in concentration. Median levels displayed in box and whisker plots. n = 19 for SVZ factors and n = 10 for hippocampal factors. Each sample was assayed in triplicate. *p < 0.005.

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Table 3.   Levels of proliferation-regulating factors that did not show regional differences in concentration. Significance set at p < 0.005; n.s., denotes non-significance. n = 19 for SVZ factors, except p16INK4a where n = 18. n = 10 for hippocampal factors, except TGF-β1 where n = 9
FactorSVZ mean ± SEM (pg/mg)Hippocampal mean ± SEM (pg/mg)Wilcoxon matched-pairs test outcome (p-value)
EGF9.25 ± 1.68 3.47 ± 0.25n.s. (0.105)
HB-EGF126.10 ± 9.98157.00 ± 10.87 n.s. (0.037)
IL-65.81 ± 1.383.67 ± 1.07n.s. (0.109)
p16INK4a3.52 ± 0.86
TGF-β166.55 ± 5.92126.90 ± 16.12n.s. (0.012)

Relationship of proliferation-regulating factor levels with age

In the hippocampus, age significantly predicted TGF-β1 levels (range: 61.44–196.22 pg/mg, b = 0.835; p < 0.01; n = 9, Fig. 2), when controlling for post-mortem interval, pH and storage time. Age accounted for 70% of TGF-β1 variance. Hippocampal levels of BDNF, EGF, FGF2, GDNF, HB-EGF, IGF-1, IL-1β, IL-6 and TGF-α were not significantly predicted by age.

image

Figure 2.  Age significantly predicted hippocampal TGF-β1 levels. Each point displays the mean ± SEM of TGF-β1 for each case, assayed in triplicate by ELISA (n = 9). **p < 0.01.

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When controlling for post-mortem interval, pH and storage time, age did not significantly contribute to regression models for SVZ levels of BDNF, EGF, FGF2, GDNF, HB-EGF, IGF-1, IL-1β, IL-6, p16INK4a, TGF-α and TGF-β1. Kolmogorov–Smirnov two-sample tests demonstrated no effect of gender on any of the factors of interest. Age did not significantly correlate with post-mortem interval, tissue storage time or pH.

Discussion

  1. Top of page
  2. Abstract
  3. Materials and methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References

Levels of proliferation-regulating factors in human adult neurogenic areas

This is the first study to measure levels of proliferation-regulating factors in the human adult SVZ. BDNF, EGF, FGF2, GDNF, HB-EGF, IGF-1, IL-1β, IL-6, TGF-α and TGF-β1 were present in the human adult SVZ in measurable levels, with FGF2 being present at levels at least 10-fold higher than any other factor. Tissue sampled from the lateral wall of the lateral ventricle in this study contained the SVZ with a small portion of underlying caudate nucleus, as the SVZ varies in width throughout its dorsal-ventral axis (Quinones-Hinojosa et al. 2006) and its boundaries are difficult to distinguish in fresh tissue. The concentration of IL-6 measured in this study was fourfold higher than that reported in the human caudate, measured using the same method as in this study (Mogi et al. 1994). Similarly, the concentration of EGF reported in this study was 2.5-fold higher than that reported in the human striatum (Futamura et al. 2002), and this difference is unlikely to be due to differences in methodology as both our study and the study by Futamura et al. (2002) report similar levels of EGF in the hippocampus. Given the discrepancy in concentrations with past studies using the human caudate or striatum alone, we believe the levels of factors measured in our tissue predominantly reflect the levels of these factors in the SVZ.

This is the first study to measure protein levels of FGF2, IL-1β, TGF-α, IGF-1, EGF and IL-6 protein in the human adult hippocampus. Levels of IGF-1 were below the minimum detection level, and similar to the SVZ, FGF2 was present in concentrations at least 20-fold higher than any other factor. Average hippocampal levels of BDNF and EGF were within the range of previously published values (Durany et al. 2000; Hock et al. 2000; Futamura et al. 2002; Karege et al. 2005). Hippocampal GDNF levels in our study were approximately 13-fold higher than that reported in a previous study (Michel et al. 2008), but that study did not use the yield-increasing acid retrieval method that was used in this study. Hippocampal HB-EGF levels in our study were approximately threefold higher than those reported in a previous study (Futamura et al. 2002), but this study used a different method to measure HB-EGF levels.

Differences between factor levels in the hippocampus and SVZ

Levels of GDNF, TGF-α and IGF-1 are significantly higher in the human SVZ than the hippocampus. The SVZ receives afferents from rich sources of GDNF, such as the substantia nigra and the caudate nucleus (Mogi et al. 2001; Hoglinger et al. 2004; Quinones-Hinojosa et al. 2006; Michel et al. 2008). These areas have higher concentrations of GDNF than the hippocampus (Michel et al. 2008). Additionally, SVZ stem cells, unlike hippocampal precursors, contact the lateral ventricle surface and are exposed to the cerebrospinal fluid (Mirzadeh et al. 2008), which contains TGF-α and IGF-1 (Mogi et al. 1996; Salehi et al. 2008).

Levels of BDNF, FGF2 and IL-1β are significantly higher in the hippocampus than in the SVZ. The higher level of hippocampal BDNF is to be expected as the hippocampus is a BDNF-rich area, with approximately double the average level of BDNF compared to many other brain areas, including frontal, parietal, temporal and occipital cortices, putamen and thalamus (Durany et al. 2000; Karege et al. 2005), and up to 15 times the level of BDNF compared with the motor and entorhinal cortices (Narisawa-Saito et al. 1996). It is not clear why levels of IL-1β and FGF2 differ between the SVZ and hippocampus. Microglia, a major source of IL-1β, in the SVZ of young adult mice have a different phenotype than microglia in other areas of the brain, including the hippocampus (Goings et al. 2006) and IL-1β can modulate FGF2 levels in adult rat brain and organotypic hippocampal cultures (Rivera et al. 1994).

Age-related expression of proliferation-regulating factors in human tissue

Hippocampal levels of TGF-β1 strongly increased with age across the whole human adult lifespan, whereas hippocampal and SVZ levels of BDNF, EGF, FGF2, GDNF, HB-EGF, IGF-1, IL-1β, IL-6 and TGF-α, and SVZ levels of p16INK4a did not vary across the adult lifespan. These results are in agreement with the only other study to measure age-related adult protein expression of a putative proliferation-regulating factor in human neurogenic zones, which reported no significant correlation between hippocampal GDNF protein levels with adult age (Michel et al. 2008). Our findings are also in agreement with studies in humans reporting no significant change in hippocampal FGF2 and BDNF mRNA levels with adult age (Weickert et al. 2005; Webster et al. 2006).

As the brain ages, microglial cells switch from a resting to an activated phenotype, and there is an age-related increase in the number of activated microglia in the human mesial temporal lobe, including the hippocampus (Sheng et al. 1998; Nichols 1999). As activated microglia may express TGF-β1 (Morgan et al. 1993; Pasinetti et al. 1993), this could result in the increased hippocampal TGF-β1 expression we have found with age.

Age-related expression of proliferation-regulating factors in non-human tissue

Although our finding of an increase in human hippocampal TGF-β1 levels with age is in accordance with a report of an increased hippocampal TGF-β1 mRNA expression with age in rats (Nichols 1999), the majority of our results from human neurogenic areas conflict with data obtained from other mammals. We found no age-related changes in human SVZ TGF-α and p16INK4a protein levels, but aged mice display lower SVZ TGF-α protein levels and higher p16INK4a mRNA levels than young adult mice (Enwere et al. 2004; Molofsky et al. 2006). Furthermore, a decrease in hippocampal FGF2 protein and GDNF mRNA levels and an increase in IL-1β and IL-6 protein levels in adult murine species have been described with age (Bhatnagar et al. 1997; Ye and Johnson 1999; Casolini et al. 2002; Terao et al. 2002; Miyazaki et al. 2003; Crivello et al. 2005; Shetty et al. 2005; Moore et al. 2007). These discrepancies may be a reflection of differing experimental designs, as these rodent studies examined factor levels only at several discreet life stages, whereas we examined expression over the whole human lifespan. Alternatively, these data may reflect differences in age-associated changes in the regulation of neurogenesis in the human brain compared with that in non-human mammals. This would not be unexpected as previous observations have identified differences between the process of neurogenesis in humans compared with non-humans, such as differences in the migratory path of neuroblasts from the SVZ to the olfactory bulb (Curtis et al. 2007b), and the absence of chain migration and migratory glial tubes in humans (Alvarez-Buylla and Garcia-Verdugo 2002; Quinones-Hinojosa et al. 2006).

Functional implications

The difference in expression levels of factors between the SVZ and hippocampus suggests the factors with predominant influence on neurogenesis in the SVZ may differ from those in the hippocampus. Regulation of bone morphogenetic protein 4, another factor important in neurogenesis, differs between these two neurogenic areas in mice, with extensive bone morphogenetic protein 4 signaling in hippocampal but not SVZ precursors (Bonaguidi et al. 2008). This is thought to underlie the limited self-renewal capabilities of hippocampal precursors, a phenomenon not seen with SVZ stem cells (Bull and Bartlett 2005; Bonaguidi et al. 2008). In a similar way, the factors examined in this study may contribute to other differences between SVZ and hippocampal neurogenesis. For example, environmental enrichment and exercise increase adult hippocampal proliferation, but not SVZ proliferation (Brown et al. 2003). The effect of environmental enrichment on neurogenesis is partly dependent on BDNF (Rossi et al. 2006) and the effect of exercise on neurogenesis is mediated by IGF-1 (Trejo et al. 2008). The current data demonstrate that levels of these factors in the SVZ and hippocampus are differentially regulated in humans.

The functional implications of the age-related patterns of proliferation-regulating factor expression on human neurogenesis remain to be characterized. The current sample of cases is well-defined, in that only cases without neuropathology (e.g. age-related Alzheimer-type neurophathologies) were assessed. Thus, the tissues investigated optimally represent selective age-related changes in a human cohort. The selective robust changes observed in the present study in only one of the factors analysed suggest that the magnitude of the age-associated change in this factor is significantly greater than those for other factors, an advantage of such a comparative analysis. Compared with the importance placed on age-related changes in FGF2, GDNF, IGF-1, IL-1β, IL-6, p16INK4a and TGF-α for the decline in neurogenesis in other mammals (Ye and Johnson 1999; Casolini et al. 2002; Miyazaki et al. 2003; Enwere et al. 2004; Shetty et al. 2005; Nishino et al. 2008), our data may suggest that in humans these factors have less influence on these processes, or that their influence occurs earlier in the lifespan of humans.

To date, age-related changes in human neurogenesis are unknown. TGF-β1 decreases proliferation of murine hippocampal progenitors (Battista et al. 2006; Buckwalter et al. 2006; Wachs et al. 2006). If TGF-β1 has similar effects on human hippocampal progenitors, then it could be predicted that the increase in hippocampal TGF-β1 with age may result in decreased levels of hippocampal progenitor proliferation with age. Whether this may result in decreased neurogenesis remains unclear as there is conflict in the literature as to whether TGF-β1 changes neurogenesis. One study has reported TGF-β1 increases neurogenesis in cultured adult rat hippocampal precursor cells (Battista et al. 2006), one study reported TGF-β1 has no effect on neuronal fate decision of hippocampal precursors (Wachs et al. 2006) and one study reported TGF-β1 decreases murine hippocampal neurogenesis in vivo (Buckwalter et al. 2006). In future work, it will be important to study how ageing affects levels of neurogenesis in each of the neurogenic regions of the human brain.

In conclusion, in the first study investigating age-related changes in proliferation-regulating proteins in human adult neurogenic zones we have demonstrated an increase in TGF-β1 levels with age in the human hippocampus. We have also demonstrated levels of BDNF, EGF, FGF2, GDNF, HB-EGF, IL-1β, IL-6, IGF-1 and TGF-α do not significantly change with age in the human adult SVZ and hippocampus, in contrast with many studies performed in mice and rats. Finally, we have shown that levels of GDNF and TGF-α are significantly higher in the SVZ than the hippocampus and levels of BDNF, FGF2 and IL-1β are significantly higher in the hippocampus than in the SVZ, suggesting that factors with predominant influences on neurogenesis differ between the two human adult neurogenic areas.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Materials and methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References

Tissues were received from the Australian Brain Donor Program’s NSW Tissue Resource Centre and Sydney Brain Bank which are supported by the Universities of Sydney and New South Wales, Neuroscience Research Australia, National Health and Medical Research Council of Australia, Schizophrenia Research Institute, and National Institute of Alcohol Abuse and Alcoholism. This project was funded by the RM Gibson Scientific Fund of the Australian Association of Gerontology, the National Health and Medical Research Council of Australia and Parkinson’s ACT. ELW is supported by a Brain Sciences UNSW Postdoctoral Fellowship. KLD and GH were recipients of Research Fellowships from the National Health and Medical Research Council of Australia. PSS is supported by an National Health and Medical Research Council of Australia Program Grant (No. 350833). The authors declare no conflict of interest.

References

  1. Top of page
  2. Abstract
  3. Materials and methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References