Age-related changes in levels of brain-derived neurotrophic factor in selected brain regions of rats, normal mice and senescence-accelerated mice: a comparison to those of nerve growth factor and neurotrophin-3
Introduction
Brain-derived neurotrophic factor (BDNF) (Leibrock et al., 1989, Ernfors et al., 1990, Hohn et al., 1990), one of a family of nerve growth factor (NGF), is abundant in the brain and supports the survival of several types of neuron, such as septal cholinergic neurons, mesencephalic dopaminergic neurons, striatal GABAergic neurons and cerebellar neurons (for review, see Hyman et al., 1991, Lindsay, 1993, Lindholm et al., 1993). Since levels of mRNA for BDNF increase with development of the rat brain (Maisonpierre et al., 1990), it has been proposed that BDNF supports the survival of neurons in the adult brain. BDNF has also attracted considerable attention as a possible therapeutic agent since levels of mRNA for BDNF and numbers of BDNF-immunoreactive neurons are lower in the hippocampus of individuals with Alzheimer’s disease than in age-matched controls (Philips et al., 1991, Schätzl, 1995, Connor et al., 1997). However, recent studies have demonstrated the absence of any gross loss of cells from brains of mice with null mutations in the gene for BDNF (Ernfors et al., 1994, Conover et al., 1995, Liu et al., 1995). Two possible explanations have been offered for these observations: the functions of BDNF might be subsumed by other trophic factors; or BDNF might have other functions in the brain, as suggested recently (Kang and Schuman, 1995, Thoenen, 1995, Akaneya et al., 1997). If it is true that BDNF supports the survival of nerve cells, it follows that depletion of BDNF should occur in the brain during normal aging, with resultant loss of neuronal cells in the aged brain. To confirm this conclusion, it is necessary to determine the levels of BDNF in various regions of brains from aged animals and to compare these levels to those in the respective regions of brains from young adult animals.
There is evidence that NGF supports the survival of cholinergic neurons in the basal forebrain (for review, see Longo et al., 1993). An intraventricular injection of NGF induces an increase in the number of cholinergic neurons, however, brains from mice with null mutations in the gene of NGF do not exhibit any gross loss of neurons in any region (Fische et al., 1991, Yunshao et al., 1991, Crowley et al., 1994, Kordower et al., 1994, Markowska et al., 1994). By contrast, there are conflicting reports on the concentrations of NGF in the hippocampus of aged rats: both decreased and unchanged levels of NGF have been reported (Lärkfors et al., 1988, Hellweg et al., 1990, Crutcher and Weingartner, 1991, Nishizuka et al., 1991). The reason for the discrepancy is unknown. We reported recently that all the BDNF in brain tissue is bound to cellular particles (Katoh-Semba et al., 1998). We also found two forms of NGF, namely, a loosely bound form that could be solubilized easily by general buffers and a tightly bound (particle-bound) form that could be solubilized only in the presence of guanidine hydrochloride (GuHCl) (Hoener et al., 1996, Katoh-Semba et al., 1997, Katoh-Semba et al., 1998). Thus, it is possible that, in some previous studies, do errors in determination of total concentrations of NGF in brain tissues from young adult and aged rats might have been introduced by use of inadequate extraction methods. We have already reported the distribution of loosely bound NGF and NT-3 in mice (Katoh-Semba et al., 1989, Katoh-Semba et al., 1990, Katoh-Semba et al., 1994, Katoh-Semba et al., 1996). Here, we report the levels of BDNF in various regions of brains from both aged rats and young adult rats as well as age-related changes in total levels of BDNF, NGF and NT-3 solubilized with GuHCl, in selected regions of brains from Sprague-Dawley rats, Crj:CD-1 mice, and senescence-accelerated mice with memory disturbances (Takeda et al., 1981).
Section snippets
Animals and chemicals
Male and female Crj:CD-1 mice and Sprague-Dawley rats were purchased from Charles River (Kanagawa, Japan) and Slc (Shizuoka, Japan), respectively. Senescence-accelerated mice P8/Ta (SAM-P8) and senescence-resistant mice r1/Ta (SAM-r1) mice were kindly provided by Prof. Toshio Takeda of Kyoto University. They were raised in our laboratory and were used at various ages. For experiments, female mice were used exclusively because of sex differences in levels of NGF in selected regions of the mouse
Concentrations of BDNF in seven regions of brains and the hypophysis from young adult and aged Sprague-Dawley rats
The highest concentrations of BDNF were detected in the hippocampus at 1 and 24 months of age (Table 2). In addition, the level of BDNF in the hippocampus from aged rats was significantly higher than that in the same region from young adult rats (260%, P<0.01). By contrast, in the cerebral cortex, septum, striatum and hypothalamus from aged rats, the concentrations of BDNF were lower than those in the respective regions from young adult rats (56, 30, 22 and 52% lower in the cerebral cortex,
Discussion
It was reported that the concentrations of BDNF mRNA, but not NGF mRNA, were lower in the hippocampus from individuals with Alzheimer’s disease than in age-matched controls (Philips et al., 1991). A more recent study using immunohistochemical techniques suggested a reduction in the level of BDNF in the hippocampus from patients with Alzheimer’s disease (Connor et al., 1997). It is generally considered that a severely impaired brain that is a result of normal aging is similar to the brain of a
Acknowledgements
This work was supported by a Grant-in-Aid for Scientific Research (no. 07680865) and a Grant-in-Aid for Scientific Research on Priority Area (no. 10176240) from the Ministry of Education, Science, Sports and Culture, Japan.
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