**4. Neuroinflammation in Alzheimer disease**

AD is a neurodegenerative disease that affects more than 20 million people worldwide and is characterized by a progressive deterioration of cognitive functions, particularly memory [43].

Currently, it is the most common cause of dementia in older adults and accounts for 50–60% of cases [44]. This disease usually begins after 65 years of age with a gradual increase in oblivion accompanied with other cognitive impairments, such as problems with calculations, visuo‐ spatial orientation, and language [45, 46]. This disease is defined as a multifactorial disorder in which genetic and environmental factors combine, but that is mostly of sporadic origin; It is estimated that only 2–10% of cases are hereditary [47, 48]. However, experts agree that the development of AD would be the result of multiple converging factors in the same case with multiple pathophysiological mechanisms explaining the cognitive impairment that causes this disease.

AD is a neurodegenerative disorder, characterized by the formation of two types of protein aggregates in the brain: senile plaques and neurofibrillary tangles (NFTs) consisting of amyloid-beta and altered tau, respectively [49]. At present, it is also considered that astroglial and microglial activation is characteristic of the disease, which in interaction with abnormal protein aggregates ultimately leads to dysfunction and neuronal death [50]. Histological evidence suggests that NFTs formed by self-aggregation of hyperphosphorylated tau protein forming paired helical filaments (PHFs) are pathognomonic for the disease; the pathology of tau is directly correlated to clinical deterioration [48, 49]. There are numerous and diverse factors such as head injuries, high fat intake, B vitamin deficiency, recurrent infections, alterations in cholesterol homeostasis, obesity and poor eating habits, among others that are able to increase the risk of developing the disorder [1, 51–55]. However, none of these risk factors seems to act as the real cause of the disease, although all are involved in its development [56].

Activation of astrocytes, internally, involves the activation of transcription factor NF-κB, which controls secretions of chemokine and adhesion molecules, and thus favors peripheral lym‐ phocyte infiltration and increases inflammatory response, which leads to neurodegeneration [36]. It has been shown that blockage of NF-κB transcriptional activity in astrocytes can extensively reduce inflammation, thus suggesting that inhibition of NF-κB in astrocytes may

With this background, it is possible to say that activated astrocytes are able to cause neurode‐ generation; moreover, when activated astrocytes express inflammation-associated factors, such as the peptide S100β, they represent a key factor for neuroinflammation. S100β is exclusively produced by astrocytes and, under physiological conditions, it is a neurotrophin responsible for survival, development, and function of neurons [39]. In neurodegenerative diseases such as AD and PD, among others, and also in subjects with severe brain trauma, the peptide S100β is overexpressed, and its levels correlate with the progression of the pathology

Another evidence linking astroglial activation with the development of neurodegenerative processes is proton resonance spectroscopy. Through this technique consistent evidence of significant increase of myoinositol (characteristic marker of astroglial cells) in neurodegener‐ ative diseases has been obtained. This has been observed both in brains of patients with mild cognitive impairment (MCI) and AD patients, and according to some studies, it has been

AD is a neurodegenerative disease that affects more than 20 million people worldwide and is characterized by a progressive deterioration of cognitive functions, particularly memory [43].

Currently, it is the most common cause of dementia in older adults and accounts for 50–60% of cases [44]. This disease usually begins after 65 years of age with a gradual increase in oblivion accompanied with other cognitive impairments, such as problems with calculations, visuo‐ spatial orientation, and language [45, 46]. This disease is defined as a multifactorial disorder in which genetic and environmental factors combine, but that is mostly of sporadic origin; It is estimated that only 2–10% of cases are hereditary [47, 48]. However, experts agree that the development of AD would be the result of multiple converging factors in the same case with multiple pathophysiological mechanisms explaining the cognitive impairment that causes this

AD is a neurodegenerative disorder, characterized by the formation of two types of protein aggregates in the brain: senile plaques and neurofibrillary tangles (NFTs) consisting of amyloid-beta and altered tau, respectively [49]. At present, it is also considered that astroglial and microglial activation is characteristic of the disease, which in interaction with abnormal protein aggregates ultimately leads to dysfunction and neuronal death [50]. Histological evidence suggests that NFTs formed by self-aggregation of hyperphosphorylated tau protein

be regarded as a potential therapy for diseases such as AD [38].

reported to correlate with progression of pathology [36, 41, 42].

**4. Neuroinflammation in Alzheimer disease**

[36, 40].

24 Update on Dementia

disease.

Furthermore, and looking for a common event in the existing hypotheses, neuroinflammation in the CNS appears as a key event in the pathophysiology of AD. Based on this, promising targets for AD treatment have emerged by regulating neuroinflammation and cross-talk mechanisms between microglia and neurons [57–59].

In this context, it becomes interesting to identify the levels of neuroinflammation and micro‐ glial activation, leading to the permanent release of cytokines, which have neurotoxic effects and are involved in the progression of this pathophysiological process [60].

In the case of AD, there is evidence to correlate high expression of inflammatory mediators in the vicinity of deposits of amyloid-beta peptide and neurofibrillary tangles, which in turn are associated with the development of neurodegeneration, exemplifying the relationship between neuroinflammation, neurodegeneration, and cell types involved [58].

As explained above, neuroinflammation is a key event in the development of AD, as it involves the different triggers of the disease. Based on this, it has been suggested that the use of antiinflammatory drugs could be beneficial and could delay the onset or progression of AD. To continue, we must at least mention the role of the cyclooxygenase (COX) enzyme. COX is an enzyme that exhibits two catalytic activities: an activity of bis-oxygenase (catalyzes the formation of prostaglandins G2 (PG) from arachidonic acid) and its second peroxidase activity (reduced PG G2 to PG H2) [61]. COX in its peroxidase activity also produces free radicals, which are partly used for the same enzyme [61]. With this information, the possible mechanism of NSAIDs in neurodegenerative diseases such as AD would be based on their inhibitory effect on brain COX. COX-1 and COX-2 enzymes are expressed in the CNS, but COX-2 plays a unique role in the brain compared to the periphery: COX-2 is expressed constitutively only in the brain, while elsewhere expression is activation dependent [27]. Although expression of this enzyme is related primarily to neurons, authors have already shown expression in astrocytes and microglia [62]. It has also been demonstrated that COX-inhibiting NSAIDs reduce microglial activation and, on the other hand, neuronal stress processes, such as ischemia and excitotoxicity, are associated with strong upregulation of neuronal COX-2 expression. This suggests that COX-2 is involved in neurotoxic mechanisms and could be an effective target for treatment [27].

NSAIDs have another non-COX-dependent mechanism that can decrease the inflammatory response through direct activation of the peroxisome proliferator-activated receptor gamma (PPARy), a nuclear transcription factor, which acts to suppress the expression of a broad range of proinflammatory genes [63], even in the microglial cell. NSAIDs act as PPARy agonists and bind to it directly giving a start to its transcriptional activity, thus inhibiting the expression of proinflammatory cytokines such as IL-6 and TNF-α secreted by microglia and astrocytes, avoiding proinflammatory activity of these cells [27, 64].

In clinical studies, comparative analyzes were performed in the brains of cognitively normal patients chronically using NSAIDs over age versus those not using NSAIDs that revealed no changes in the appearance of senile plaques, but there was a threefold decrease in the number of activated microglia in the brains of chronic users of NSAIDs [65]. AD patients who used NSAIDs compared with another group of patients who did not use NSAIDs showed a significantly slower progression of disease [66]. These findings are correlated with the above and suggest that the protection provided by the chronic use of NSAIDs in AD patients may be derived at least partially from the attenuation of microglial activation [58].

Despite all these favorable results, we cannot overlook the fact that clinical trials of NSAIDs for patients with cognitive impairment and AD did not show clear results, and the observed effects vary depending on the cognitive instrument that is used. For example, the results indicate that the NSAID naproxen reduced cognitive decline in some patients but caused acceleration in cognitive decline in other patients. Conversely, celecoxib (another NSAID) appears to have similar, but attenuated effects in AD patients [67]. Therefore, it is still prema‐ ture to make clinical recommendations, despite the positive results. However, positive findings open new avenues of research with significant clinical potential in order to develop an effective treatment for AD and other diseases with neuroinflammatory components.

On the other hand, as a result of the lack of efficacy of current treatments for AD, and based on the positive results obtained in patients taking anti-inflammatory drugs, a new possibility has opened up the study of the association of inflammatory processes and pathophysiology of AD.

A new form of prevention against the neuroinflammatory process, and thus also an interesting way to prevent neurodegenerative brain damage, is based on changes in diet and the con‐ sumption of nutritional supplements, functional foods, and nutraceuticals.

An interesting example of such food supplements is a new naturally occurring compound with high concentrations of antioxidants and anti-inflammatory properties called Andean Com‐ pound (initially called as Shilajit Andino). The Andean Compound is a very complex mixture of humic substances, generated by the decomposition of ancient plant material; it is originated as an endemic natural product of the Andes Mountains. Its main active principle is fulvic acid [68]. According to studies by Cornejo et al., fulvic acid is able to block tau self-aggregation affecting the length and morphology of PHFs generated *in vitro*, projecting as a good support for the treatment of AD. Also, after exposure of preformed tau fibrils to fulvic acid, a decrease in the length of PHFs can be detected [69]. So, this compound emerge as a novel nutraceutical with potential uses against neurodegenerative brain disorders [69].

The formation of tangles has been identified as a key and convergent event among many of the factors involved in the neurodegenerative process. Our multidisciplinary research group is currently working on a new nutraceutical containing Andean Compound plus B vitamins (B6, B9, and B12 vitamins) named Brain-Up 10®. Patients who have participated in a pilot clinical trial showed a trend toward lower cognitive impairment, a reduction in neuropsy‐ chological symptoms, and less distress for the caregiver. The appearance of new com‐ pounds that can open the way to new treatments becomes a necessity. In this search, compounds such as Andean Compound, which, because of their natural origin and the lack of adverse effects, appears as a promising therapy against neurodegenerative diseases, can give strong evidence that their effects are mediated by disruption of the inflammatory re‐ sponse and self-aggregation of the tau protein [58].
