**5. Impact on brain morphology, plasticity, and cognition**

Arias [36] in isolated astrocytes obtained from brain cortex of 1- to 3-day-old Wistar rats, they found astrocyte activation, An increase on the expression of amyloid precursor protein (APP), and promoted its amyloidogenic processing, and an increase in reactive species oxygen (ROS), a marker of oxidative stress, after treating the culture for 48 h with cholesterol concentrated at 25 or 50 μM. All these parameters measured, including glia activation, resemble features that have been found in postmortem brain tissues obtained from AD patients [37–39], but how the consumption of a diet high in cholesterol can contribute to the development of AD? *In vivo* studies can answer this question. Transgenic mice Tg2576 (which express the human APP695 carrying the Swedish double mutation at codons 595 and 596, Hsiao et al. [40]), were fed with a 5% cholesterol diet for 6 weeks. They found an increase of the APP cytosolic fragment but apparently the hypocholesteremia induced by the diet does not deregulates Aβ metabolism

In a further work, carried out by Refolo et al [41], with 5-months-old double-mutant for presenilin (PS) and amyloid precursor protein (PSAPP) mice, which express familial mutant PS1M146V and the APP695 mutations [42], evaluated the effect of a combined diet with 5% cholesterol and 10% fat for 7 weeks. They found that the dietary treatment induced elevated levels of cholesterol in both, plasma and brain, which is an important data since it showed that brain cholesterol is produced *in situ*, and this data demonstrates that brain cholesterol is increased by diet. This increase in brain cholesterol correlates with an increase of total Aβ in brain. In addition, there was an enhanced amount of Aβ, particularly not in Aβ 1–40 and 1– 42, but in 1–30 and 1–34 as well. This was accompanied with an increase in the number of Aβ deposits as well as an increase in the plaque area in the hypercholesteremic transgenic mice. Interestingly, there were no changes found in presenilin 1 (PS1) processing. These data strongly supported the hypothesis that a diet high in fat and cholesterol can contribute to the

**Figure 3.** As result of consume diets high on fat and cholesterol there is an increase levels of brain cholesterol and sys‐ temic cholesterol. Also elevates A*β* production in brain and its deposit and increases as well the glia activation and

All these data shows experimental evidence linking the consumption of diets rich in fat and/or cholesterol with the development of amyloidosis. Nevertheless, dementia is a more complex syndrome, comprised of many other features such as cognitive decline and neuronal lost. Particularly in the hippocampus, which is as we mentioned before, one of the first areas affected during the neurodegenerative process, its susceptibility to suffer alterations resulted from consuming diets high in fat or cholesterol appears crucial as one of the possible mecha‐

development of amyloidosis, one of the main conditions to develop AD.

production of ROS in brain. All these together can lead to AD onset.

(George et al, 2004).

56 Update on Dementia

In the last sections, we have discussed how the consumption of diets rich in fat or cholesterol can contribute to the production of Aβ peptide in noncerebral tissue. The impact that this could have in the BBB selective permeability and its participation in brain amyloidosis conditions that can contribute to the dementia onset but, besides these alterations, one of the main conditions found in dementia patients is brain atrophy and behavioral alterations. Is brain functionality affected by the components typically found in the Western diet? Could diet composition affect brain architecture and plasticity? Moreover, is cognition affected the consumption of diets rich in fat or cholesterol? We will review such ideas in the current section.

A link between cognitive decline and dietary habits has been proposed. There is an epidemio‐ logical study carried out with Japanese men living in Hawaii compared with age-matched men living in Japan that evaluated the prevalence of dementia employing the Diagnostic and Statistical Manual of Mental Disorders. The results found that those subjects living in the USA have a higher prevalence of dementia: 9.3% for all type dementia, 5.4% for Alzheimer's disease, and 4.2% for vascular [43]. Continuing in this line of evidence, there is another study that was carried out with people from same ethnic background living in their natal land or in a foreign country (USA). They found in concordance with the study cited before, that those individual living in Indiana (where the study was carried out on) had a higher prevalence of dementia compared with age-matched individuals living in Nigeria or Ibadan [44]. This data strongly suggests that there are some stimuli in this Western country, which contribute to the devel‐ opment of several types of dementia, and the question is: what are these stimuli? A good candidate are the nutritional habits. In Western countries, especially countries such as the USA or Mexico, people consume food with high amounts of saturated fat and cholesterol and show the highest rates of obesity worldwide. The brain is an organ rich in lipids and essential fatty acids that are mainly obtained from food and have a crucial participation on brain functioning [45]. So, to think that lipids elevation induced by diet could be in detriment of the brain, which is a logical assumption, but what are the cellular mechanisms involved in the possible detrimental effect of food components such as fat and cholesterol? Well, experimental work has demonstrated evidence of the interplay between obesity, brain alteration, and cognitive decline, more especially with hippocampal-related cognitive processes. Seminal works in this area were carried out in the University of Toronto by Greenwood and Winocur [46]. They fed 1-month-old Long-Evans rats with two types of high-fat diets containing 40% of calories: a saturated fatty acids (lard-based) or a polyunsaturated fatty acids (soybean oil-based) and compared with a standard laboratory diet containing 4.5% of fat. They tested learning and memory abilities in the rats after 3 months of dietary treatment with the radial arm maze test, the variable-interval delayed alternation task, and the Hebb-Williams maze series. These tests evaluate spatial learning and memory performance and report failures in working or reference memories. They found that those animals fed with the lard-based diet showed impairment in all the tests. Following this line of evidence, they analyzed further with different types of saturated fatty acid diets: monounsaturated (MUFA) and polyunsaturated (PUFA) fatty acids, finding a direct relationship between the 3 months consumption of saturated fatty acids and failures in basic alternation rule, and remembering trial-specific information over time in the variable-interval delayed alternation task. Interestingly, they found alterations in brain's phosphatidylcholine fatty acid profile. However, the changes in the membrane did not correlate with cognitive alterations [47]. It suggested there is another mechanism elucidating the cognitive impairment related to consumption of diets rich in fat; a good candidate is brain inflammation. Chronic inflammation is one of the principal altered events associated with AD [48], and it has been linked to obesity and has been reported that there is a correlation between both, obesity and AD [49, 50]. Middle-aged C57BL6 male mice were fed for 21 weeks with chow equivalent to Western diet containing 41% fat or a high-fat lard diet containing 60% fat for 16 weeks. They showed an alteration on learning acquisition measured by the Stone T-maze and it is accompanied by microglial activation, increase expression of cytokines like TNFα, IL-6, and MCP-1, and a decrease on brain-derivated neurotrophic factor (BNDF) [51]. Inter‐ estingly, there was not any detrimental effect observed in those animals that consumed the like-Western diet. These data agree with results from Greenwood and Winocur and propose a possible way underlying the effect diet, which is an inflammation process, and the decrease on neural factors crucial for learning processes. The results demonstrate that diet can interfere with learning abilities, but is it everything behind the diet effect on cognitive decline? There is a report with 344 white middle-aged male Fischer rats. The researchers evaluate the effect of a diet high in cholesterol and fat (diet containing 2% cholesterol and 10% hydrogenated coconut oil). The results showed a failure in working memory, here evaluated with the water radial arm maze as well as elevated lipids profile and reduce expression of Map-2 as an indicator of alteration of dendritic integrity, which correlates with memory mistakes measured in the test, and increase in inflammation markers such as microglia activation [52]. In a study carried out with Sprague-Dawley rats, which were fed for 7 days with high fat and fructose, several hippocampal alterations, such as decreased insulin signaling, were reported. In addition, they found that treated animals had a decrease in hippocampus total weight in addition with some other morphological alterations such as a diminishment on the number of dendritic spines and a reduction in the complexity of the hippocampal dendritic arborization. Moreover, there was a decrease in the expression of the microtubule-associated protein 2 (MAP-2) and in the content of synaptophysin in the CA1 region concomitant with an increased phosphorylation of tau protein, and in the presence of reactive astrocyte associated [53]. It directly demonstrates alterations in hippocampal cytoarchitecture that definitively have a strong impact on brain functionality, especially in hippocampal-related learning and memory processes.

Another feature which affected by consuming diets rich in fat is adult hippocampal neuro‐ genesis (AHN). Adult neurogenesis is a highly specialized plasticity phenomenon that, under basal conditions, occurs in two restricted brain areas: a) the subventricular zone and b) the hippocampal dentate gyrus [54, 55]. Hippocampus is a crucial area for memory processes, since its decrease is associated to memory failures, especially in short-term memory, spatial memory, and learning flexibility [56–59]. The AHN is a complex process that comprises several devel‐ all the tests. Following this line of evidence, they analyzed further with different types of saturated fatty acid diets: monounsaturated (MUFA) and polyunsaturated (PUFA) fatty acids, finding a direct relationship between the 3 months consumption of saturated fatty acids and failures in basic alternation rule, and remembering trial-specific information over time in the variable-interval delayed alternation task. Interestingly, they found alterations in brain's phosphatidylcholine fatty acid profile. However, the changes in the membrane did not correlate with cognitive alterations [47]. It suggested there is another mechanism elucidating the cognitive impairment related to consumption of diets rich in fat; a good candidate is brain inflammation. Chronic inflammation is one of the principal altered events associated with AD [48], and it has been linked to obesity and has been reported that there is a correlation between both, obesity and AD [49, 50]. Middle-aged C57BL6 male mice were fed for 21 weeks with chow equivalent to Western diet containing 41% fat or a high-fat lard diet containing 60% fat for 16 weeks. They showed an alteration on learning acquisition measured by the Stone T-maze and it is accompanied by microglial activation, increase expression of cytokines like TNFα, IL-6, and MCP-1, and a decrease on brain-derivated neurotrophic factor (BNDF) [51]. Inter‐ estingly, there was not any detrimental effect observed in those animals that consumed the like-Western diet. These data agree with results from Greenwood and Winocur and propose a possible way underlying the effect diet, which is an inflammation process, and the decrease on neural factors crucial for learning processes. The results demonstrate that diet can interfere with learning abilities, but is it everything behind the diet effect on cognitive decline? There is a report with 344 white middle-aged male Fischer rats. The researchers evaluate the effect of a diet high in cholesterol and fat (diet containing 2% cholesterol and 10% hydrogenated coconut oil). The results showed a failure in working memory, here evaluated with the water radial arm maze as well as elevated lipids profile and reduce expression of Map-2 as an indicator of alteration of dendritic integrity, which correlates with memory mistakes measured in the test, and increase in inflammation markers such as microglia activation [52]. In a study carried out with Sprague-Dawley rats, which were fed for 7 days with high fat and fructose, several hippocampal alterations, such as decreased insulin signaling, were reported. In addition, they found that treated animals had a decrease in hippocampus total weight in addition with some other morphological alterations such as a diminishment on the number of dendritic spines and a reduction in the complexity of the hippocampal dendritic arborization. Moreover, there was a decrease in the expression of the microtubule-associated protein 2 (MAP-2) and in the content of synaptophysin in the CA1 region concomitant with an increased phosphorylation of tau protein, and in the presence of reactive astrocyte associated [53]. It directly demonstrates alterations in hippocampal cytoarchitecture that definitively have a strong impact on brain functionality, especially in hippocampal-related learning and memory

Another feature which affected by consuming diets rich in fat is adult hippocampal neuro‐ genesis (AHN). Adult neurogenesis is a highly specialized plasticity phenomenon that, under basal conditions, occurs in two restricted brain areas: a) the subventricular zone and b) the hippocampal dentate gyrus [54, 55]. Hippocampus is a crucial area for memory processes, since its decrease is associated to memory failures, especially in short-term memory, spatial memory, and learning flexibility [56–59]. The AHN is a complex process that comprises several devel‐

processes.

58 Update on Dementia

opmental steps starting from the division of an endogenous neural precursor cell followed by its expansion, differentiation, and fully integration to the hippocampal network [60]. These steps are reported as number of proliferative cells measured by markers of cell division; cell fate decision with the marker of early differentiation, the cytoeskeleton protein doublecortin (DCX) that is expressed in newly differentiated cells, and with NeuN, a nuclear marker of granular cells when the cell is fully differentiated. It has been recently documented that there are some food components which can regulate the neurogenic process (for a review [61]). The hippocampal neurogenesis has captured the attention since it was described in 1965 by Dass and Altman [62] due, as we already mentioned, the hippocampus is closely related to memory as well as neurodegenerative processes. Juvenile male and female Sprague-Dawley rats under a dietary regimen of high- (42% coconut butter and corn oil fat) or low-fat diet (10% fat by energy) or standard laboratory chow for 4 weeks, was found that males under high-fat diet show less cell proliferation than females and reported elevated levels of corticosterone, a stress hormone [63]. Differences in AHN were studied in mice susceptible to develop obesity (C57BL/ 6N) and obesity resistant (C3H/HeN). They were fed with high- and low-fat diet finding that those animals that developed obesity and consumed the high-fat diet had much lower number of proliferative cells and cells committed to neural linage (DCX positive cells), which establish a clear link between obesity and AHN diminishment [64]. In our laboratory, we have observed that 8 weeks of diet rich in fat (60%) or high in cholesterol (1.4%) in 5-months-old male Wistar rats has an impact on AHN in both, cell proliferation and more especially in the morphology of DCX cells. These cell populations have less processes and a poor complexity than animals under normal laboratory diet, and we found alterations in short-term memory (Leal-Galicia and Meraz-Ríos data *not yet published*). All these data together strongly suggest a detrimental effect on diets rich in fat or cholesterol in cognitive components such as navigation memory, working memory, acquisition learning, and short-term memory suggesting as mediators, alterations in brain cytoarchitecture and AHN, and associates obesity with such cognitive alterations strongly supporting the hypothesis that obesity can lead to development of dementia **(Figure 4)**.

**Figure 4.** The intake of food with high amounts of fat or cholesterol produces alteration in the hippocampus such as: reduced expression of Map-2, reduction on the number of dendritic spines and in the complexity of the dendritic tree and a decrease on neurogenesis. Consume diets with these components has also a functional impact in short-term memory, working memory and learning flexibility, that could contribute to the detriment observed in the dementia syndrome.
