**4. Impact of a diet rich in cholesterol or fat on the development of AD onset**

The hippocampus is a brain structure considered as a part of the allocortex, which is one of the oldest brain areas from the phylogenetical point of view. It has a high capacity of plasticity; it is directly involved in learning and memory process and, interestingly, is very susceptible to damage and has attracted the research focus for several years since it is one of the first brain structures that degenerate during the AD process [35]. As we reviewed in the last section, the hippocampus seems to be very susceptible to the effect of consumed diets rich in fat or cholesterol, but can this actually drive the brain into a degenerative process? Can it contribute to the development of dementia? We will discuss this idea in the current section. First, we will review how the diet high in cholesterol or fat can contribute to the development of features associated with AD, particularly with amyloidosis.

Diets rich in cholesterol, as we have reviewed, can induce vascular inflammation, BBB, and promotes Aβ peptide accumulation in the brain parenchyma in an animal model of rabbit fed with high-cholesterol diet [26–28]. Supporting the association of elevated concentrations of cholesterol and AD detriment in a very recent *in vitro* study carried out by Avila-Muñoz and

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 (George et al, 2004).

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

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

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‐ nism involved in the development of AD **(Figure 3)**. We will discuss that idea in the section below.
