**2. Findings on amyloid-β production induced by saturated fat diet in noncerebral tissue**

One of the histopathological hallmarks of AD is the extracellular deposition of amyloid-β peptide (Aβ) in the brain. It is widely accepted that Aβ deposition occurs when the neuronal synthesis of the peptide exceeds the clearance capacity [3, 4]. However, some decades ago, the idea was proposed that Aβ generated systemically could pass the BBB and be deposited in the brain, since Aβ was detected in noncerebral biological fluids. Such idea raised from grounding data of Seubert et al. [5], who demonstrated that Aβ fragment comprising the amino acids 13– 28 can be detected in cerebrospinal fluid and plasma of several species including human as well as in conditioned media from human brain cell cultures. It originated the idea that cerebral Aβ deposits could be generated systemically and for unknown mechanism, accumulate in the brain where they affect the capacity, to be clear, increasing the amount of the peptide and eventually form the extracellular deposits. A good amount of data has focused on this idea **1. Introduction**

50 Update on Dementia

**noncerebral tissue**

In the recent decades, the population in the industrialized Western countries has become remarkable sedentaryandhavehada considerable increase inthe intakeofwhathasbeencalled "fast food," meals that are rich in fat and carbohydrates and contain elevate levels of cholester‐ olaswell.The elevatedconsumptionoffastfoodhashadastrongimpactonpublichealth,which has importantrepercussions in several levels including an economic impact due to the elevated cost of a chronic use of specialized health services and a detrimental effect in both, life quality and expectancy for the patients. Among the adverse health effects of this type of diet, we can mention obesity, vascular diseases, and metabolic syndrome, and it has been recently pro‐ posed that it can increase the risk of developing Alzheimer's disease (AD), which is the most common type of dementia in elderly people. It is considered that a particular type of diet could accelerate the progress of the disease for a not yet well-known mechanism [1]. It is a revolu‐ tionary idea, since we have had for several years the conception that brain is actually protect‐ ed by the blood–brain barrier (BBB); however, experimental evidence suggests that the consumption of diets rich in fat can disrupt the permeability of BBB, making it vulnerable to

In the current chapter, we will review the state of the art related to the impact of diets rich in fat or cholesterol on the brain, and how the alterations induced in other organs can impact brain functioning and could increase the susceptibility to develop dementia. The bibliographic revision was carried out running an exhaustive search on the research articles related to the topic employing the database of the US National Library of Medicine, National Institutes of Health, PubMed.gov. Firstly, reviewing the most recent papers and those with the most relevant information. Thereafter, we carefully followed the references cited by the reviewed articles in order to study the grounding data on the subject and which direction it followed

systemic molecules that could trigger degenerative processes [1, 2].

until our days in order to document the accuracy and evolution of the data.

**2. Findings on amyloid-β production induced by saturated fat diet in**

One of the histopathological hallmarks of AD is the extracellular deposition of amyloid-β peptide (Aβ) in the brain. It is widely accepted that Aβ deposition occurs when the neuronal synthesis of the peptide exceeds the clearance capacity [3, 4]. However, some decades ago, the idea was proposed that Aβ generated systemically could pass the BBB and be deposited in the brain, since Aβ was detected in noncerebral biological fluids. Such idea raised from grounding data of Seubert et al. [5], who demonstrated that Aβ fragment comprising the amino acids 13– 28 can be detected in cerebrospinal fluid and plasma of several species including human as well as in conditioned media from human brain cell cultures. It originated the idea that cerebral Aβ deposits could be generated systemically and for unknown mechanism, accumulate in the brain where they affect the capacity, to be clear, increasing the amount of the peptide and eventually form the extracellular deposits. A good amount of data has focused on this idea

since then. An interesting line of study has focus on the production of Aβ by noncerebral tissue induced by consumption of diets rich in fat. One of the physiological functions of Aβ is relate to lipids metabolism and many Aβ transport proteins have been associated with lipids *in vivo* [6]. The association of the Aβ soluble fraction with high-density lipoproteins from healthy human plasma and cerebrospinal fluid was reported as well [7, 8]. The association between lipids and Aβ was demonstrated in a very elegant study where Aβ activity was followed labeling it with radioactivity, and it was found that the peptide is expressed in tissues rich in fat, such as spleen, marrow, liver, adipose tissue, brain, kidney, lung, and skeletal muscle. It was shown that the expression of Aβ is associated with postprandial lipoproteins such as chylomicrons, lipoproteins that are in charge to move dietary fat from intestine to the target organs. These associations remain during lipolysis and tissue uptaking processes [9]. There‐ fore, it can be proposed that an increased plasmatic amount of such proteins containing Aβ could produce an imbalance and could even be delivered in brain contributing to cerebral amyloidosis, one of the responsible events related to Alzheimer's disease [9, 10]. The natural question is: how can we increase the amount of Aβ associated to postprandial lipids? One answer is the intake of diets rich in fat or cholesterol because they could break the balance of lipids content, but by which way? An interesting direction has been to study the expression of Aβ in organs rich in lipids and if such expression is regulated by fat or cholesterol diets.

Koudinov et al. [11] reported that hepatocytes secrete amyloid-β as a lipoprotein complex. Another organ where it has been documented that Aβ is produced is the small intestine. Given the evidence that Aβ is associated to postprandial lipoproteins, chylomicrons, Galloway et al. [10] followed this line of evidence and studied small intestinal epithelial cells (where the chylomicrons are produced). They fed wild-type mice with low- or high-fat diet. After six months of treatment they determinate by immunohistochemistry, the expression of the amyloid precursor protein in absorptive cells in the small intestine and observed a greater expression of this molecule in small intestinal epithelial cells of high-fat fed animals, whereas animals fasting 65 h did not show any expression. There is another study where the group of John CL Mamo evaluated the expression of Aβ in enterocytes after a low- or high-fat diet with 1% cholesterol in apoliprotein E (apo E) (-/-) knockout mice. Apoliprotein E is a lipoprotein that modulates Aβ biogenesis [12–14]. After six months of dietary treatment, the small intestine of apo E (-/-) KO mice fed with low-fat diet showed the same levels of expression of Aβ as the wild-type animals detected by immunohistochemistry. On the other hand, both groups of animals, wild-type and apo E (-/-) KO mice fed with high-fat diet, showed an increased expression of Aβ in enterocytes being higher in the KO animals. Also in these study, the group evaluates villi length between the groups treated, finding that the high-fat diet did not affect villi length in apo E(-/-) KO mice, but interestingly there is an increase in villi length of KO mice treated with low-fat diet when compared with wild-type mice under the same dietary conditions [15]. These groups also carried out a very elegant study to corroborate the associ‐ ation of Aβ production with recently generated lipoproteins, employing three-dimensional immunofluorescence microscopy and determinated that Aβ produced by enterocytes certainly has a clear colocalization with chylomicrons in small intestine enterocyte after three months of dietary treatment (free of cholesterol). They found that the amount of Aβ colocalizing with chylomicrons reaches the double [16]. These data together confirms the presence of Aβ in 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 Aβ to brain and induce cerebral amyloidosis.

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