**4. The Protective Role of BDNF on Neurodegeneration**

Neurodegenerative diseases comprise a wide range of neurological diseases such as AD, PD, Huntington's disease, and amyotrophic lateral sclerosis (ALS), characterized by the deterioration and then the death of selective nuclei of neurons in the brain or the spinal cord. They are chronic and progressive diseases, currently incurable and highly debilitating, causing a tremendous emotional and economic burden on patients, their families, and society. AD, the most frequent among neurodegenerative diseases, accounts for about 70% of dementia cases all over the world, that is about 35 million people. It is estimated to cost more than 480 billion euros each year throughout the world (Sources: OMS, EBC (European Brain Council)). Currently, no pharmacological treatment is available to cure or even significantly slow down the course of neurodegenerative diseases. For these reasons, experimental findings showing that physical exercise, exposure to an enriched environment, metabolic changes and nutritional and/or cognitive intervention, may exert a protective role on neurodegeneration either by delaying the onset and/or curbing the course of the disease, raise hope that these new tools might be useful also in clinical practice. BDNF appears to be crucial or, in some cases even essential, to mediate the neuroprotective effects of the above-mentioned environmental stimuli (Figure 3). In particular, as discussed above, it is well established that BDNF accounts for the hippocampal adult neurogenesis, which, in turn, can be stimulated by a number of conditions such as physical exercise, enriched environment, hormonal balance (i.e., steroid hormones such a cortisol and testosterone) and nutritional intervention (i.e., fasting, low-calorie intake, low-carb diet, selective nutrient intakes), capable of increasing the BDNF level [241].

**Figure 3.** The molecular mechanisms mediated by BDNF involved in depression, Alzheimer's disease, and glioma. External stimuli (stress, maternal deprivation, or lack of activity) causing epigenetic regulation processes can induce a reduction in BDNF expression level and in neuronal activity.

This results in atrophy, neuronal death, and cognitive decline, which may contribute to depression or Alzheimer's disease. In these pathologies the BDNF/TrkB signaling, which activates the downstream Akt and ERK signaling, is altered. Thus, such alterations cause an impairment of CREB signaling resulting in BDNF downregulation. The alteration of phosphorylation (P) inhibits (red X) the transcriptional machinery. In the mouse brain, environmental enrichment induces an increase of BDNF. BDNF, binding the truncated form of TrkB receptor (TrkB.T1), signals directly to the Rho protein dissociation inhibitor (GDI). The latter detaches from TrkB.T1 and binds to the small G protein RhoA, leading to an inhibition of glioma cell migration. BDNF stimulates also indirectly the production of IL-15 in microglia, which in turn stimulates the natural killer cells to produce IFN-γ. IFN-γ contributes to reducing glioma growth.

#### *4.1. The Protective Role of BDNF on Alzheimer's Disease*

A reduced level of BDNF has been found in patients affected by neurodegenerative diseases such as Parkinson's, Huntington's and Alzheimer's disease as well as in mild cognitive impairment, the latter being a prodromal stage of AD, characterized by a slight decline of cognitive abilities including memory, thinking and judging skills [242–245]. In some instances, the levels of BDNF even correlate with the severity of the diseases, pointing towards a pathogenetic link between BDNF and AD [246]. Although there are some papers reporting an increase of BDNF in serum or in the post-mortem brain, this might be due either to compensatory mechanisms or its release from immune cells or pharmacological treatments known to raise BDNF (i.e., antidepressants) [241].

Recently, a very complex study explored the role of physical activity in a genetic mouse model of AD. This study provided the most compelling evidence of the relationship between physical activity, adult hippocampal neurogenesis, BDNF, and AD. This study elegantly confirms that adult hippocampal neurogenesis plays a pivotal role in brain resilience to AD. They manipulated with pharmacological and genetic tool neurogenesis as well as BDNF, clearly showing that physical exercise needs neurogenesis to protect the brain from AD and that BDNF is essential for such a protection. In addition, it provides evidence that adult hippocampal neurogenesis can counteract AD memory impairment, only in combination with BDNF, whereas if neurogenesis is experimentally blocked, BDNF does not exert beneficial effects. Finally, pharmacological increase of BDNF further ameliorates AD pathology [247]. Thus, agents that promote both BDNF signaling and neurogenesis might be the key to preventing or curing AD. As far as metabolism is concerned, it has been shown that intermitting fasting, by causing a transition from utilization of carbohydrate and glucose to a fatty acid and ketones source of energy (refer to as "G-K shift") generates a number of beneficial cognitive, metabolic, and cardiovagal effects. BDNF is increased upon intermitting fasting and mediates at least part of these effects. Its increase is stimulated by the ketone body, β-hydroxybutyrate that inhibits histone deacetylases that repress BDNF promoters [248]. Recently, the role of BDNF and neuroprotection in the context of metabolism and fasting has been nicely reviewed by Mattson et al. [6].

### *4.2. BDNF and Ras-ERK-CREB Signaling in Alzheimer's Disease*

BDNF, as also discussed above, causes the activation of the Ras-ERK signaling cascade leading to the phosphorylation of CREB. Such a pathway exerts a well-known trophic and protective role on neuronal cells both in vitro and in vivo in a variety of neurodegenerative models, including AD, PD, and Huntington's diseases. Nevertheless, it has become clear that the Ras-ERK pathway may also foster neurodegeneration or hamper the action of neurotrophic factors when activated by noxious stimuli as occurs for instance in PD and AD [249]. In particular, it has been shown in a number of different cellular models such as primary cortical rat neurons, rat B103 neuroblastoma cells, and A1 mouse mesencephalic cells, that APP and/or Aβ42 oligomer induces the activation of Ras-ERK and GSK-3 signaling, that, in turn, causes hyperphosphorylation of tau and APP at Thr668. The involvement of these molecular events in the pathogenesis AD is corroborated by the finding that activation of Ras-ERK and GSK-3 correlates with Aβ levels in the brain of AD patients [250,251]. Aberrant stimulation of Ras-ERK signaling forces neurons to enter the cell cycle as shown by the expression and nuclear accumulation of cyclin D1 and the subsequent G1/S progression. Since neurons lack functional cell

cycle machinery, these events lead to cell death (i.e., mitotic catastrophe) instead of cell division. Interestingly, as clearly shown in the mouse model of familial AD APPswe/PS1ΔE9 mice, although ERK phosphorylation is enhanced compared to the wild type counterpart, it does not result in normal CREB phosphorylation. The impairment in CREB signaling parallels to impairment in a number of cognitive tests [252]. Therefore, in AD, BDNF downregulation is mediated by the impairment of CREB signaling caused by amyloid β [253] (Figure 3).
