**3. Effect on vascularity and BBB integrity**

The brain is a very well-protected organ with two barrier systems. One is a highly specialized microvascular endothelial system known as blood brain barrier (BBB), its function is to protect the brain from the entry of damaging substances and at the same time, allows the entry of nutrients as well as endocrine signals by means of an active transport and a passive diffusion system. The second is the choroid plexus, whose function is to prevent the entry of blood in the cerebrospinal circulation [17]. An unbalance in such systems could lead to disease condi‐ tions regarding the entrance of damaging molecules or disrupting the entrance of proper nutrients or endocrine signals. A good body of data has focused in study; how dietary habits can trigger BBB disruption? A longitudinal study, carried out in Sweden, evaluated the integrity of BBB *in vivo* in 81 women with a wide range of body size, who acceded to receive a lumbar puncture in order to obtain cerebrospinal fluid and compared the index of albumin content. Albumin is a constitutive protein that is absent in the brain, since its access is stopped by the BBB; therefore its presence in cerebrospinal fluid is a sign of disruption of the protection systems. Among these large group studied, the obese and overweight women between 70 and lipoproteins generated in small intestine and that a diet rich in fat could increase the production of transport lipoproteins. However, the open question stills remains: how this Aβ produced systemically reaches the brain? **(Figure 1)**. Further studies are necessary to establish if indeed an imbalance in lipids production induced by diet can promote the delivery of these systemic

**Figure 1.** The ingestion of food rich on fat and cholesterol can increase the amount of postprandial lipoproteins chylo‐ microns. An increased production of chylomicrons can lead to an overproduction of A*β* and potentially produce an

The brain is a very well-protected organ with two barrier systems. One is a highly specialized microvascular endothelial system known as blood brain barrier (BBB), its function is to protect the brain from the entry of damaging substances and at the same time, allows the entry of nutrients as well as endocrine signals by means of an active transport and a passive diffusion system. The second is the choroid plexus, whose function is to prevent the entry of blood in the cerebrospinal circulation [17]. An unbalance in such systems could lead to disease condi‐ tions regarding the entrance of damaging molecules or disrupting the entrance of proper nutrients or endocrine signals. A good body of data has focused in study; how dietary habits can trigger BBB disruption? A longitudinal study, carried out in Sweden, evaluated the integrity of BBB *in vivo* in 81 women with a wide range of body size, who acceded to receive a lumbar puncture in order to obtain cerebrospinal fluid and compared the index of albumin content. Albumin is a constitutive protein that is absent in the brain, since its access is stopped by the BBB; therefore its presence in cerebrospinal fluid is a sign of disruption of the protection systems. Among these large group studied, the obese and overweight women between 70 and

Aβ to brain and induce cerebral amyloidosis.

52 Update on Dementia

unbalance on A*β* processing and lead to cerebral amyloidosis.

**3. Effect on vascularity and BBB integrity**

84 years had the highest amount of albumin reported as the ratio of albumin in cerebrospinal fluid/Serum albumin (CSF/S albumin). Interestingly, they found a correlation between low levels of sex hormone binding globulin (SHBG) in the same group of women when they were younger [18]. It is known that SHBG decreases with overweight in both, male and female [19– 21]. In the Swedish longitudinal study, SHBG was employed as measure of endocrine signal in the same group of females when they were in there middle forties, and decades later when they were analyzed for several parameters besides the CSF/S albumin ratio, such measures included behavioral evaluations finding that they had cognitive alterations [18]. It strongly suggests that since youth, these group of obese and overweighting women had less content of SHBG accompanied in elderly years by BBB disruption and cognitive decline. These data suggest that an unbalance between the selective entrance and exit of molecules and signaling drived by a failed BBB filtering can lead to development of dementia, but more experimental data is needed in order to elucidate the mechanism behind this effect. One way to explain the cognitive detriment found in these patients could be the diminishment of factors that have been shown to be protective for the brain, such as SHBG. High levels of SHBG have been associated with neuroprotection in stroke, vascular and cardiovascular diseases, diabetes [21– 25], and an increased amount of molecules potentially damaging for the brain, such as Aβ [26– 28]. Such idea can be supported by the fact that it was found in the obese and overweight women, a higher ratio of CSF/S albumin has been observed in subjects with AD as well [29, 30]. In this study, the CSF/S albumin content was measured in 118 patients diagnosed with AD and clinical data of vascular alterations was registered as well. The AD subjects were compared with individuals without dementia of the same age, finding a higher albumin ratio in those with both AD and vascular factors. There was not significant BBB disruption in the patients without vascular alterations; additionally, there is no correlation with BBB distur‐ bances and age in the control group, which strongly suggests a relationship with the vascular alterations, BBB disruption, and AD [29]. Controversially in a study, albumin content as well as IgG in serum and cerebrospinal fluid in several groups of patients with different dementias such as early-progression familial AD, the senile dementia of Alzheimer type (Late Onset Alzherimer's Disease LOAD), and two types of vascular dementia: a group diagnose with vascular dementia and others with multiinfarct, were measured. The multiinfarct group was reported with the highest significant alteration of the BBB but not in AD group. All these data supports the idea that vascular factors associated to BBB disruption are in relationship with the development of many dementia syndromes and are not restricted to AD [31]. That controversial information can be clarified with animal experimental data, where several variables can be controlled. The very first experimental evidence that the Aβ peptide can actually cross BBB and be deposited in the brain parenchyma was done in 1993 by Zlokovic et al. [32]. The researchers injected synthetic forms of Aβ peptide: 1–28 and 1–40, which were labeled with a radioactive marker in order to follow it after carrying out an injection in the neck vessel of the guinea pigs. The research group found a specific deposition of both synthetic peptides in the BBB microvasculature, initiating in the luminal side and transcellular transport into the brain parenchyma. This study strongly supports the idea that the Aβ produced systemically can cross the BBB. However, the mechanism remains unclear so far.

Although there is evidence that BBB can be disrupted in patients with dementia, it is possible that the development on AD can be due to systemically produced Aβ that can cross the BBB and form the deposits in the brain, but how does this happen? As we reviewed, obese patients apparently have a disrupted BBB permeability, although, what triggers that? Are the intake habits involved in such phenomenon? There is experimental evidence that suggest that components of Western diet, such as cholesterol and saturated fat, can contribute to that phenomenon. Studies with rabbits fed with a diet containing 2% cholesterol for 8 weeks, have demonstrated that such type of diet disrupts BBB permeability, alters vascularity, and induce vessels inflammation and Aβ peptide accumulation in parenchyma [26–28]; and this accumu‐ lation is similar to that observed in brains of AD patients [33]. This body of data, mainly generated by D.L. Sparks and collaborators, strongly supports the idea that high cholesterol consumption, importantly, contributes to the development of AD onset by the accumulation of Aβ, vascular alterations, as well as BBB selective permeability disruption.

The contribution of BBB disruption of a high energetic diet (HE) (approximately 40% Kcal of fat versus 13% of standard laboratory rodent diet) based on high saturated fat and glucose was evaluated in 60-days-old 32 male rats that were fed for 90 days with this type of diet. The researchers evaluated the BBB integrity, measuring by ELISA, the content of sodium fluores‐ cein (NaFl) injected throughout the femoral artery in the prefrontal cortex, striatum, and hippocampus of the treated rats. They found a significant increased amount of NaFl in the hippocampus of the treated rats compared with the control but not in prefrontal cortex or in striatum. They also measured the mRNA expression of tight junction proteins by RT-PCR in choroid plexus and BBB capillaries. Thigh junction proteins are critical components for maintenance of selective BBB permeability, its diminishment can alter the BBB function. They found a decrease expression of the thigh junction proteins and alterations in behavioral task directly associated with hippocampal function [1]. A further study was carried out by Davidson et al. [34], where they fed 24 male rats with a high energy diet as well as high saturated fat and glucose and following for different time points (7, 14, 21 and 28 days), evaluated BBB integrity by injecting NaFl following the same procedure reported by Kanoski et al. [1]. They found that the hippocampus was the brain structure that exhibit the highest concentration of the dye compared with prefrontal cortex and striatum. In this study, the researchers evaluate the differences between those animals, under HE diet, that show what they called *obesity resistant* versus those that developed obesity. The obesity resistant group was the one that consumed the HE diet but gained the least weight and body fat. The animals included in the obesity group were those that gained the most bodyweight and fat. It was this last group that showed the major BBB permeability and had the highest deposit of NaFl in the hippocampus. Interestingly, they found that those animals, in the HE diet, had the lowest bodyweight and the lowest amount of fat, and did not show difference in the behavioral performance compared with the control group. However, those rats that developed obesity and had the higher deposit of dye in the hippocampus, showed alterations in the performance of the hippocampal-dependent tasks [34]. These evidences directly shows a relationship between diets rich in fat, obesity development, and hippocampal-related cognitive alterations. We will discuss in the next section, the relevance of the hippocampal structure, cognitive performance, and its detriment.

From the information reviewed in this section, we can conclude that BBB alteration is a feature that takes part of dementia onset in both, AD and vascular dementia. Obesity can contribute to this phenomenon and, although the mechanism is not well known, a particular factor that can participate in this process is the intake of diets rich in cholesterol or fat, as well as glucose, those known components of a typical Western diet **(Figure 2)**.

Although there is evidence that BBB can be disrupted in patients with dementia, it is possible that the development on AD can be due to systemically produced Aβ that can cross the BBB and form the deposits in the brain, but how does this happen? As we reviewed, obese patients apparently have a disrupted BBB permeability, although, what triggers that? Are the intake habits involved in such phenomenon? There is experimental evidence that suggest that components of Western diet, such as cholesterol and saturated fat, can contribute to that phenomenon. Studies with rabbits fed with a diet containing 2% cholesterol for 8 weeks, have demonstrated that such type of diet disrupts BBB permeability, alters vascularity, and induce vessels inflammation and Aβ peptide accumulation in parenchyma [26–28]; and this accumu‐ lation is similar to that observed in brains of AD patients [33]. This body of data, mainly generated by D.L. Sparks and collaborators, strongly supports the idea that high cholesterol consumption, importantly, contributes to the development of AD onset by the accumulation

The contribution of BBB disruption of a high energetic diet (HE) (approximately 40% Kcal of fat versus 13% of standard laboratory rodent diet) based on high saturated fat and glucose was evaluated in 60-days-old 32 male rats that were fed for 90 days with this type of diet. The researchers evaluated the BBB integrity, measuring by ELISA, the content of sodium fluores‐ cein (NaFl) injected throughout the femoral artery in the prefrontal cortex, striatum, and hippocampus of the treated rats. They found a significant increased amount of NaFl in the hippocampus of the treated rats compared with the control but not in prefrontal cortex or in striatum. They also measured the mRNA expression of tight junction proteins by RT-PCR in choroid plexus and BBB capillaries. Thigh junction proteins are critical components for maintenance of selective BBB permeability, its diminishment can alter the BBB function. They found a decrease expression of the thigh junction proteins and alterations in behavioral task directly associated with hippocampal function [1]. A further study was carried out by Davidson et al. [34], where they fed 24 male rats with a high energy diet as well as high saturated fat and glucose and following for different time points (7, 14, 21 and 28 days), evaluated BBB integrity by injecting NaFl following the same procedure reported by Kanoski et al. [1]. They found that the hippocampus was the brain structure that exhibit the highest concentration of the dye compared with prefrontal cortex and striatum. In this study, the researchers evaluate the differences between those animals, under HE diet, that show what they called *obesity resistant* versus those that developed obesity. The obesity resistant group was the one that consumed the HE diet but gained the least weight and body fat. The animals included in the obesity group were those that gained the most bodyweight and fat. It was this last group that showed the major BBB permeability and had the highest deposit of NaFl in the hippocampus. Interestingly, they found that those animals, in the HE diet, had the lowest bodyweight and the lowest amount of fat, and did not show difference in the behavioral performance compared with the control group. However, those rats that developed obesity and had the higher deposit of dye in the hippocampus, showed alterations in the performance of the hippocampal-dependent tasks [34]. These evidences directly shows a relationship between diets rich in fat, obesity development, and hippocampal-related cognitive alterations. We will discuss in the next section, the relevance of the hippocampal structure, cognitive

of Aβ, vascular alterations, as well as BBB selective permeability disruption.

performance, and its detriment.

54 Update on Dementia

**Figure 2.** The overproduction of systemic A*β*, produced by consume diets rich on fat or cholesterol, can promote and alter the selective permeability of BBB, allowing the passage of molecules to the brain, such as systemic A*β* that was not clear and lead to cerebral amyloidosis and brain inflammation.
