**3. Concluding remarks**

ulation and mitochondrial protection [153, 165]. Other multi-target potential treatments currently under development for AD are based on the use of the following compounds: **•** *Caffeine*: This is one of the most consumed psychoactive drugs which mainly acts blocking adenosine receptors 1 and 2 [290, 291]. In addition, caffeine reduces amyloid burden in animal models of AD [292, 293]. Epidemiological studies in humans have also shown

**•** *Estrogen*: This steroid hormone is known to play an important role in neuronal survival, mitochondrial function, neuroinflammation and cognition, with important neuroprotective effects [297-299]. Some of the neuroprotective actions mediated by estrogens are related to the insulin-like growth factor-1 (IGF-1) signaling pathway [300]. Several studies in animal models of AD have revealed therapeutic properties of estrogen against the progression of the disease. For instance, the treatment of ovariectomized 3xTg-AD mice with estrogen resulted in prevention of the increased Aβ accumulation and worsening memory perform‐ ance induced by the depletion of sex steroid hormones [301]. Clinical and epidemiological studies in AD support the beneficial effets of estrogens [302]. However, a critical factor for success in estrogen therapy for AD is the age at the initiation of the treatment; the efficacy of estrogens is greatest in younger women and in women who initiated the estrogen therapy

**•** *Cannabinoids*: The natural compounds derived from *Cannabis sativa* or synthetic compounds acting on endogenous cannabinoid system have emerged as potential agents against several neurodegenerative processes [305]. Cannabinoids offer a multi-faceted approach for the treatment of AD as the stimulation of the widely brain-expressed cannabinoid receptors provides neuroprotection against Aβ [305, 306] and reduces neuroinflammation [306-308] and tau phosphorylation [306, 309] in AD-like transgenic mice. In addition, cannabinoids support brain repair mechanisms by augmenting neurotrophin expression and enhancing neurogenesis [310]. Moreover, cannabinoids are able to reduce Aβ-dependent oxidative stress [311] and Aβ-mediated lysosomal destabilization related to apoptosis [312]. In addition, some cannabinoids are able to inhibit acetylcholinesterase activity [313]. It is worth stressing that molecular achievements of cannabinoids are accompanied by cognitive improvement and reduction of several degenerative markers in two different animal models of AD [306, 308]. Examination of the potential beneficial effects of chronic administration of low doses of cannabinoids with little psychotropic effect at early stages of the degenerative

**•** *Erythropoietin (EPO) and derivatives*: EPO is effective in neuroprotection against ischemia and traumatic brain injury [314]. In addition, animal studies reveal that EPO both reduces tau phosphorylation through modulation of PI3K/Akt-GSK-3beta pathway [315] and protects against Aβ-induced cell death through anti-oxidant mechanisms [316]. An additional characteristic of EPO that confers potential utility in AD is the specific effect on cognition: EPO enhances hippocampal LTP and memory by modulating plasticity, synaptic connec‐ tivity and activity of memory-related neuronal networks [317]. In spite of these benefits, chronic administration of EPO is problematic because of the concomitant excessive eryth‐ ropoiesis. In this sense, some new derivatives of EPO that do not bind to the classical EPO

protection against cognitive decline [294-296].

272 Understanding Alzheimer's Disease

at the time of menopause [303].

process in humans seems very promising.

Main targets of therapeutic intervention at early stages of Alzheimer are summarized in Figure 1. Based on the presently available data several conclusions can be drawn. Combination therapies with drugs targeting different pathological factors or the use of multi-target com‐ pounds appear to be the most effective strategy in the treatment of the neurodegenerative process in Alzheimer. Most potential experimental therapies exhibit the highest efficiency when applied during the pre-symptomatic phase of the disease. Therefore, it is essential to develop diagnostic tools to detect Alzheimer at early stages. Moreover, considering that Alzheimer, as a degenerative process not necessarily leading to dementia, affects a large percentage of individuals in the sixth decade of life, it would be wise to introduce habits and low-cost, safe treatments to prevent the progression of Alzheimer early in life, as occurs in artheriosclerosis, to transform AD into a chronic, incomplete and non-devastating disease thereby allowing for normal life in the elderly.

beneficious at first stages of the degenerative process may be harmful at advanced stages. Special effort must be put into practice to learn about the combination of drugs

Potential Therapeutic Strategies to Prevent the Progression of Alzheimer to Disease States

http://dx.doi.org/10.5772/54783

275

Parts of the work used in this review were supported by the project BESAD-P (Instituto Carlos III), Mutua Madrileña and Agrupación Mútua. We wish to thank T. Yohannan for editorial

Institut de Neuropatologia, Hospital Universitari de Bellvitge, Universitat de Barcelona,

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at which determinate time for every particular individual.

**Acknowledgements**

assistance.

**Author details**

CIBERNED, Spain

**References**

Ester Aso and Isidre Ferrer\*

\*Address all correspondence to: 8082ifa@gmail.com

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**Figure 1.** Schematic representation of the main cellular targets that are currently under development to prevent or retard the progression of Alzheimer to disease states. Most of the experimental approaches are designed to block or mitigate (red lines) pathological events occurring at the earliest stages, including abnormal Aβ and tau aggregation, chronic inflammatory responses, and oxidative stress damage. Other strategies (blue lines) aim at stimulating the me‐ tabolism to reduce Alzheimer's energetic failure as well as to promote intrinsic mechanisms that protect or repair cel‐ lular damage, including synaptic plasticity, preservation of the lipid membrane composition, and the promotion of damaged protein and organelle turnover. Therapeutic approaches based on the modulation of neurotransmission (green dashed lines) are designed to bypass deficient cholinergic neurotransmission whereas other compounds aim to block glutamatergic excitotoxicity. Considering the complex scenario of the Alzheimer neurodegenerative process, multi-target therapies applied at early stages of the disease appear to be the most effective strategy.

In addition to these general conclusions, several points deserve a particular comment. Recognition of the genotypic background, clinical and neuropathological subtypes and different pace of clinical manifestations is important to refine personalized treatments [333-335]. This includes modifications of the treatment as Alzheimer is not a mere accu‐ mulation of defects but rather a combination of deficiencies and plastic changes that im‐ ply shifts in molecular pathways with disease progression. Drugs and treatments beneficious at first stages of the degenerative process may be harmful at advanced stages. Special effort must be put into practice to learn about the combination of drugs at which determinate time for every particular individual.
