**5. Effect of ω-3 DHA/EPA on brain cognition**

As neurons are the structural and functional units of brain, electrochemical properties of the neurons allow them to transmit signals over long distances and send information to each other. Neurons form the basis of the brain activity and brain cognition and dictate the whole body when and how to work and maintain the behavior of the animals, including humans. Numerous reports have been published stating that the PUFAs have colossal roles in brain growth and development, learning, and memory. At the same time, deficiency of PUFAs such as DHA has been reported to cause neurodegeneration leading to impairments of memory and brain cognition.

Henriksen et al., reported that the level of DHA was low in the preterm infants (born at <33 weeks gestation, body weight < 1.5 Kg). Concurrently, the preterm infants had learning disabilities, reduced IQ, and weak visuospatial relations. However, when these infants were supplemented with DHA, they exhibited normal growth and development in terms of body weight, height, head circumference, visual acuity, and mental development [69]. The study thus suggests that DHA is important before birth. Infants (9-month-old, growth spurt period) fed with DHA-supplemented traditional formula showed higher problem-solving activities, when compared with those fed with traditional formula-only, suggesting thus that DHA also plays an important role during growth spurts and development [70]. Infant's gray matter autopsy (of human/ nonhuman primate) study showed that brain DHA levels have also 40% higher in the DHA-supplemented formula-fed infants than those in the formula-fed only infant brains [29, 71]. In addition, DHA declines in aging and age-related neurodegenerative diseases such as Alzheimer's disease [72–74]. All these investigations thus suggest that DHA is important for brain cognitions, such as learning and memory, thought processes, tracing of new information, and comprehension, and that brain DHA deficiency can be recovered by the dietary DHA supplementation. Though cerebral endothelial cells and brain astroglial cells can synthesize DHA and/or α-LLN, EPA from the diet can act as precursors for the DHA; however, the endogenous synthesis or conversion of DHA is extremely low [75] . Thus, dietary DHA is the ultimate source for the DHA in the brain.

We have previously reported that oral administration of DHA for 12 weeks significantly increased the learning-related memory, as evaluated by the 8-armed-radial maze task in DHA-deficient young and old rats [76, 77]. Not only DHA increases the memory of DHA-deficient young and old rats, DHA

**21**

**Figure 7.**

*ameliorated by the oral administration of DHA.*

pathways [87].

*Fatty Acids: From Membrane Ingredients to Signaling Molecules*

also had an extraordinary ability to increase the learning-related memory of Alzheimer's disease model rats [78, 79] (**Figure 7**). EPA also increased the learning-related memory, however, only after their conversion into DHA [80]. The roles of ω-6 AA on the brain cognitions have also recently been investigated; however, the results are controversial. Memory-enhancing effect of AA has been reported previously [81]. In our investigation, the ω-6 AA failed to increase memory of rats (yet unpublished). DHA always exhibited a positive effect on memory. However, the mechanisms by which DHA increases the memory remain to be clarified. Numerous mechanisms of action of DHA on memory have been proposed. DHA-induced increases in synaptic plasma membrane fluidity [26]; antioxidative effects [76–79]; anti-apoptotic effect [78]; increased expressions memory-related proteins, including postsynaptic PSD-95, presynaptic synaptophysin, NMDA-receptor unit NR2A [75], and c-fos [82]; and reductions of brain Aβ-burdens [83] have been attributed to the beneficial effects of DHA in the normal and AD rats, respectively. To examine the mechanism(s) of the reduction of amyloid burden, we tested whether DHA affects the *in vitro* Aβ peptide (Aβ25–35, Aβ1–40, and Aβ1–42 are the most toxic amyloids) fibrillation, a process that assumes to increase the Aβ deposition in the brains. We found that DHA inhibits *in vitro* Aβ fibrillation both at the initial stage of Aβ-seed formation and oligomerization and also causes dissolution of mature Aβ peptide fibers [84–86] (**Figure 8A**). It is thus conceivable that DHA, by decreasing the amyloid fibrillation, decreases the brain Aβ-burden and hence contributes to the amelioration of memory of AD model rats. DHA also caused a clearance of circulating Aβs by increased lipid raft-dependent degradation

We later tested whether DHA affects neurogenesis, which is of great interest in the modulation of memory both in the aging and neurodegenerative Alzheimer's disease. As expected, DHA accelerated both *in vitro* and

*Effect of oral administration of DHA on the learning-related memory of DHA-deficient young/old and Alzheimer's disease model rats. Protein levels of postsynaptic density protein (PSD-95), brain-derived neurotropic factor (BDNF), and presynaptic synaptophysin were measured. Also, the mRNA levels of BDNFreceptor tyrosine Kinase B (TrkB) and NMDA receptor units NR2A and NR2B were determined by RT-PCR to examine whether they were affected by the oral administration of exogenous DHA. All these parameters were* 

*DOI: http://dx.doi.org/10.5772/intechopen.80430*

#### *Fatty Acids: From Membrane Ingredients to Signaling Molecules DOI: http://dx.doi.org/10.5772/intechopen.80430*

*Biochemistry and Health Benefits of Fatty Acids*

increase in oxidative stress [68].

cognition.

**5. Effect of ω-3 DHA/EPA on brain cognition**

are numerous reports on the beneficial effects of EPA and DHA on muscle. Therefore, the effects of these PUFAs on muscle strength have been investigated with increasing interest. Hess et al. [64] reported that dietary algae and marine fish increase the levels of EPA and DHA in the equine skeletal muscles. Guen et al. [65] reported that DHA-enriched supplementation improves endurance exercise capacity and skeletal muscle mitochondrial function in murine skeletal muscle. Stebbins et al. [66] reported that DHA + EPA enhances skeletal-muscle blood and vascular conductance in active skeletal muscle (especially type I and IIa fibers) and that the increase in muscle blood is due to an increase in cardiac output secondary to increases in vascular conductance [66]. However, we believe that there are differential effects of PUFAs on the muscle [67]. AA deposition in the fast-twitch muscle of aging rats reduced cell volume with an

As neurons are the structural and functional units of brain, electrochemical properties of the neurons allow them to transmit signals over long distances and send information to each other. Neurons form the basis of the brain activity and brain cognition and dictate the whole body when and how to work and maintain the behavior of the animals, including humans. Numerous reports have been published stating that the PUFAs have colossal roles in brain growth and development, learning, and memory. At the same time, deficiency of PUFAs such as DHA has been reported to cause neurodegeneration leading to impairments of memory and brain

Henriksen et al., reported that the level of DHA was low in the preterm infants (born at <33 weeks gestation, body weight < 1.5 Kg). Concurrently, the preterm infants had learning disabilities, reduced IQ, and weak visuospatial relations. However, when these infants were supplemented with DHA, they exhibited normal growth and development in terms of body weight, height, head circumference, visual acuity, and mental development [69]. The study thus suggests that DHA is important before birth. Infants (9-month-old, growth spurt period) fed with DHA-supplemented traditional formula showed higher problem-solving activities, when compared with those fed with traditional formula-only, suggesting thus that DHA also plays an important role during growth spurts and development [70]. Infant's gray matter autopsy (of human/ nonhuman primate) study showed that brain DHA levels have also 40% higher in the DHA-supplemented formula-fed infants than those in the formula-fed only infant brains [29, 71]. In addition, DHA declines in aging and age-related neurodegenerative diseases such as Alzheimer's disease [72–74]. All these investigations thus suggest that DHA is important for brain cognitions, such as learning and memory, thought processes, tracing of new information, and comprehension, and that brain DHA deficiency can be recovered by the dietary DHA supplementation. Though cerebral endothelial cells and brain astroglial cells can synthesize DHA and/or α-LLN, EPA from the diet can act as precursors for the DHA; however, the endogenous synthesis or conversion of DHA is extremely low [75] . Thus, dietary DHA is the ultimate source for the DHA in

We have previously reported that oral administration of DHA for 12 weeks

significantly increased the learning-related memory, as evaluated by the 8-armed-radial maze task in DHA-deficient young and old rats [76, 77]. Not only DHA increases the memory of DHA-deficient young and old rats, DHA

**20**

the brain.

also had an extraordinary ability to increase the learning-related memory of Alzheimer's disease model rats [78, 79] (**Figure 7**). EPA also increased the learning-related memory, however, only after their conversion into DHA [80]. The roles of ω-6 AA on the brain cognitions have also recently been investigated; however, the results are controversial. Memory-enhancing effect of AA has been reported previously [81]. In our investigation, the ω-6 AA failed to increase memory of rats (yet unpublished). DHA always exhibited a positive effect on memory. However, the mechanisms by which DHA increases the memory remain to be clarified. Numerous mechanisms of action of DHA on memory have been proposed. DHA-induced increases in synaptic plasma membrane fluidity [26]; antioxidative effects [76–79]; anti-apoptotic effect [78]; increased expressions memory-related proteins, including postsynaptic PSD-95, presynaptic synaptophysin, NMDA-receptor unit NR2A [75], and c-fos [82]; and reductions of brain Aβ-burdens [83] have been attributed to the beneficial effects of DHA in the normal and AD rats, respectively. To examine the mechanism(s) of the reduction of amyloid burden, we tested whether DHA affects the *in vitro* Aβ peptide (Aβ25–35, Aβ1–40, and Aβ1–42 are the most toxic amyloids) fibrillation, a process that assumes to increase the Aβ deposition in the brains. We found that DHA inhibits *in vitro* Aβ fibrillation both at the initial stage of Aβ-seed formation and oligomerization and also causes dissolution of mature Aβ peptide fibers [84–86] (**Figure 8A**). It is thus conceivable that DHA, by decreasing the amyloid fibrillation, decreases the brain Aβ-burden and hence contributes to the amelioration of memory of AD model rats. DHA also caused a clearance of circulating Aβs by increased lipid raft-dependent degradation pathways [87].

We later tested whether DHA affects neurogenesis, which is of great interest in the modulation of memory both in the aging and neurodegenerative Alzheimer's disease. As expected, DHA accelerated both *in vitro* and

#### **Figure 7.**

*Effect of oral administration of DHA on the learning-related memory of DHA-deficient young/old and Alzheimer's disease model rats. Protein levels of postsynaptic density protein (PSD-95), brain-derived neurotropic factor (BDNF), and presynaptic synaptophysin were measured. Also, the mRNA levels of BDNFreceptor tyrosine Kinase B (TrkB) and NMDA receptor units NR2A and NR2B were determined by RT-PCR to examine whether they were affected by the oral administration of exogenous DHA. All these parameters were ameliorated by the oral administration of DHA.*

**Figure 8.**

*Effect of incubation of DHA on in vitro amyloid beta (Aβ) peptide fibrillation (A) and in vitro neurogenesis in NSCs culture (B) and, effect of oral administration of in vivo neurogenesis (C). Neurogenesis occurred primarily in the dentate gyrus (DG) region.*

*in vivo* neurogenesis [88] (**Figure 8B, C**), which is conducive to inhibition of the impairments of memory in aging and/or AD model rats. DHA stimulated the differentiation of neural stem cells into mature neurons by triggering the activating-type bHLH transcription factors, including neurogenin, Mash1, and NeuroD and inhibiting the repressor-type transcription factor Mes1 [89]. We also reported that DHA-derived docosanoids, such as neuroprotectin D1, help increase the memory of rats [90]. Consistent with our results, Bazan et al. [91] also reported that endogenous signaling by DHA-derived mediators sustains neuronal function and protects synapses and circuits, thus demonstrating that DHA and/or its docosanoid products might act as signaling molecules during memory processing. Finally, DHA is essential for the growth and development of brain and might play crucial roles in the formation of learning-related brain cognition.
