ReviewNew insights into brain BDNF function in normal aging and Alzheimer disease
Introduction
Aging is a multifactorial process determined by genetic and epigenetic factors resulting in a broad functional decline including endocrine, immunological and cognitive functions. Thus, most aging individuals show gradual impairment of cognitive capabilities which are associated with hippocampus or cortical alterations, two brain regions involved in learning and memory processes. Diagnostic criteria of age-associated memory impairment in humans were proposed by Crook et al. (1986). Nevertheless, changes in memory with age can be variable between individuals and all types of memory are not affected equally. In general, optimal cognitive functions are linked to efficient neuronal plasticity. The plasticity concept has highly evolved from the pioneer studies of Hebb (1949). Nowadays, some clever definitions have been proposed, notably that of Thoenen (1995) who stated that plasticity “is the capacity of neurons or glial cells to improve or to depress the synaptic efficacy through biochemical or morphological changes which evolve in a dynamical fashion”. This property is markedly decreased with aging and in pathological disorders such as Alzheimer disease (AD). There is accumulating evidence that neurotrophins are important molecular mediators of structural and functional plasticity (McAllister et al., 1999, Schinder and Poo, 2000, Thoenen, 2000, Lu et al., 2004, Arancio and Chao, 2007, Lynch et al., 2007, Tanaka et al., 2008) and also protect neurons against different kinds of brain insult (Lindvall et al., 1994, Tapia-Arancibia et al., 2004). One of these neurotrophins, i.e. BDNF and its receptors TrkB, is highly expressed in brain areas exhibiting a high degree of plasticity (i.e. the hippocampus, hypothalamus and cortex), regulates synaptic transmission, and in turn their expression is regulated by neuronal activity (Tapia-Arancibia et al., 2004).
New evidence discussed in this article suggests that some types of learning training can also stimulate not only BDNF levels but the whole BDNF metabolism as well as TrkB receptor expression in aged rats. Besides, exogenous administration of BDNF can counteract the in vitro and in vivo neurotoxic effects of β-amyloids, which are well known pathological agents in AD.
Section snippets
BDNF and neuronal plasticity
Two models of synaptic plasticity have been particularly studied: long-term potentiation (LTP) and long-term depression (LTD). The LTP concept considered as a substrate for memory (Lynch et al., 2007) was introduced by Bliss and Lomo in the early 1970s on the basis of studies on the hippocampus (Bliss and Lomo, 1973). They found that the efficacy of synaptic transmission, as measured by the size of the post-synaptic field potentials, was potentiated for several hours following a short, high
BDNF gene and its receptors
The rodent BDNF gene was initially described by Timmusk et al. (1993) and consisted of four 5′-exons (I–IV) linked to separate promoters and one 3′-exon (V) encoding the mature BDNF protein. More recently, Pruunsild et al. (2007) and Aid et al. (2007) have identified new splice variants in human and rodents, respectively, showing that at least 11 different BDNF transcripts can be generated from the mammalian rodent BDNF gene by alternative splicing (Fig. 1). The activation of different BDNF
Distribution of BDNF and its receptors in the CNS
In adult rat brain, BDNF mRNA is expressed in the hippocampus, septum, hypothalamus, cortex and in adrenergic brain stem nuclei (Castren et al., 1995, Katoh-Semba et al., 1997). BDNF immunoreactivity is also widespread in adult rat brain, including cerebral cortex, hippocampus, basal forebrain, striatum, hypothalamus, brainstem and cerebellum (Kawamoto et al., 1996) where it was visualized in soma, dendrites and fibers. In addition, in rat hippocampus, amygdala and cingulated, parietal and
BDNF system during normal aging
Plasticity is markedly reduced with aging (Burke and Barnes, 2006). During normal aging in spite of minor changes in hippocampal morphology (Barnes, 1994) impairments in LTP have been reported (Pang and Lu, 2004, Rex et al., 2005). The reader will find valuable information on the effects of aging on LTP and cognition in very informative reviews on this topic (Lynch et al., 2006, Rosenzweig and Barnes, 2003). Spatial learning can become impaired without evidence of neuron loss. These changes
BDNF and Alzheimer disease
Growing evidence suggest that a decrease in BDNF levels could be associated with AD pathogenesis (Fumagalli et al., 2006). Alzheimer disease (AD) is a progressive neurodegenerative disorder characterized by mild cognitive impairment at onset and deficits in multiple cortical functions in later stages. In the dementia stages, numerous senile plaques and neurofibrillary tangles are observed accompanied by deficits in axonal transport and neuronal loss. Indeed, the neuropathological hallmarks of
Protective effect of BDNF against β-amyloid-induced toxicity
The mechanisms by which amyloid peptides are neurotoxic are not yet understood and attempts to find protective molecules are exciting and promising. Although a substantial body of evidence has shown that BDNF protects neurons against cellular damage (Knüsel et al., 1992, Lindvall et al., 1994), we recently provided direct evidence demonstrating that BDNF has neuronal protective effects against Aβ peptide neurotoxicity in vivo and in vitro in rats (Arancibia et al., 2008). The protective effect
Conclusion and prospects
Altogether, the data examined here clearly show that BDNF and/or its receptors are impaired with aging and in AD patients. They also show that β-amyloid peptides jeopardize BDNF production and its signaling in vitro and in vivo. This fact probably engenders a dysfunctional encoding state in neurons contributing and leading to neurodegeneration (Tong et al., 2004). BDNF signaling might be impaired early in the course of AD (Murer et al., 1999). On the contrary, the exogenous addition of BDNF can
Acknowledgments
The studies from our own laboratories referred in this article were supported in part by the INSERM (France), the program ECOS-CONICYT No. C04B06 (France–Chile) end from grants from FONDECYT (Chile) (Grant #1040306) and DIPUV (Valparaiso, Chile) (15/2006, CI-1-2006).
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