**Abstract**

Alzheimer's disease is an age-related progressive neurodegenerative disorder. The two major neuropathologic hallmarks of Alzheimer's disease (AD) are extracellular Amyloid beta (Aβ) plaques and intracellular neurofibrillary tangles (NFTs). A number of additional pathogenic mechanisms, possibly overlapping with Aβ plaques and NFTs formation, have been described, including inflammation, oxidative damage, iron dysregulation, cholesterol metabolism. To date, only symptomatic treatments exist for this disease, all trying to counterbalance the neurotransmitter disturbance. To block the progression of the disease they have to interfere with the pathogenic steps responsible for the clinical symptoms, including the deposition of extracellular amyloid β plaques and intracellular neurofibrillary tangle formation, inflammation and stem cell. In this review, we discuss new potential disease-modifying therapies for AD that are currently being studied in phase I–III trials.

**Keywords:** Alzheimer, secretase modulators, anti-amyloid agents, stem cell

#### **1. Introduction**

Alzheimer's disease (AD) is an age-related progressive neurodegenerative disorder characterized by progressive memory loss, cognitive impairment and functional decline. AD is described as a multifactorial disease and several mechanisms significant roles in disease pathogenesis. Through an improved understanding of the molecular mechanisms underlying pathogenesis of AD, it is possible to develop novel, effective therapeutic methods in order to prevent onset and progression of AD. A better understanding of the molecular mechanisms underlying pathogenesis of AD makes available to a basis for development of novel, effective therapeutic strategies to prevent onset and progression of AD.

The formation of intracellular neurofibrillary tangles that are composed of hyperphosphorylated tau proteins [1] and accumulation of extracellular amyloid plaques are the fundamental neuropathological changes noticed in AD brain. Aβ and tau are two key/important proteins, have a main function in the pathogenesis of AD. Amyloid cascade hypothesis and tau hypothesis have been based on the causative factors in AD pathogenesis. While one of these hypothesis proposes that AD starts with the accumulation of Aβ, the other one suggests that AD starts with the accumulation of p-tau.

Amyloid cascade hypothesis: in 1992 Hardy and Higgins constructed the amyloid-cascade hypothesis [2]. According to this hypothesis, formation of pathological Aβ plaques, neurofibrillary tangles, synaptic loss, neurodegeneration and ultimately dementia in AD are caused by a cascade harming synapses and neurons has been triggered by Aβ and its aggregates. Aβ peptides are natural products of brain metabolism. AD is associated with the disruption of the balance between production and clearance of Aβ. Aβ accumulation in the brain induces oxidative stress and inflammatory response thus leads to neurotoxicity which contributes to impairment of cognitive functions. Several pathological events like excitotoxicity, synaptic and mitochondrial dysfunction, loss of calcium homeostasis, endoplasmic reticulum stress, oxidative stress and inflammation may occur as a result of Aβ aggregates. In spite of the role of Aβ in AD, only amyloid-cascade hypothesis is not sufficient to explain AD pathogenesis, because removal of Aβ did not halt AD pathology [3].

Tau hypothesis: tau is an intracellular protein which is a member of microtubuleassociated proteins family. This protein family promotes microtubule assembly and stabilization. Tau has neurotoxic effects when hyperphosphorylated due to loss of its normal function. Hyperphosphorylated tau promotes the formation of paired helical filaments which would eventually evolve into NFTs, dystrophic neurites, and neuropil threads [4]. Abnormal hyperphosphorylation of tau is a component of neurofibrillary tangles that is a key player of neurodegeneration and has been isolated from AD brain in the 1990s [5].

Although both hypotheses suggest primal roles of Aβ and tau protein in AD pathogenesis, increasing evidence suggests that there may be a crosstalk between two pathologies. However, the mechanisms linking Aβ toxicity and tau hyperphosphorylation have not been exactly clarified yet.

### **2. Pathogenic mechanisms in Alzheimer's disease**

#### **2.1 Oxidative stress**

Oxygen metabolism generates free radicals such as reactive nitrogen species (RNS) and reactive oxygen species (ROS) including superoxide anion and hydroxyl radical. One of the early changes observed in AD patients is increased oxidative damage. It has been shown that the percentages of 8-hydroxydeoxyguanosine (8OHdG) and 8-hydroxyguanosine (DNA and RNA oxidation markers), 4-hydroxynonenal, and F2-isoprostanes (lipid peroxidation markers), protein carbonyls and 3-nitrotyrosine (protein oxidation markers), and malondialdehyde (MDA), have been increased in AD brains [6]. Although the data is highly limited, oxidative stress may also influence hyperphosphorylation and polymerization of tau protein. Although oxidative stress has an important role in AD, it is still disputed whether it plays a causative role in the disease or secondary to the pathological changes observed in AD [7].

#### **2.2 Neuroinflammation**

Neuroinflammation is described as a process involving activation of natural immunity in the brain. The functions of neuroinflammation can be explained as protecting central nervous system from infectious insults, injury or diseases. Microglia are has a significant role in neuroinflammation. Transgenic animal models of AD have demonstrated that neuroinflammation is enhanced around amyloid plaques [8]. According to Bellucci et al. inflammation is the key player in the tauopathies for neurodegeneration [9]. It has been shown that production of enzymes

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*Future Treatment of Alzheimer Disease DOI: http://dx.doi.org/10.5772/intechopen.85096*

**2.3 Metal toxicity**

researches in the field of AD.

**2.4 Mitochondrial dysfunction**

in mitochondrial dysfunction in synapse, indirectly.

**2.5 Brain insulin resistance and insulin deficiency**

strated in neither mild nor moderate forms of AD [11].

(COX-2) and proinflammatory cytokines (IL-1β) are boosted in tau-positive nerve cells in spinal cord and brainstem. Pursuant to these results of the research, neuroinflammation might be triggered through NFTs by activating microglia. It is found that suppression of neuroinflammation is related to improvements in behavioral and cognitive deficits in AD mouse models and is in harmony with decline in hyperphosphorylated tau and Aβ plaques in brain. It is efficient to treat with interleukin-1β (IL-1β) antibodies or anti-tumor necrosis factor-α (anti-TNF-α) in order to reduce the pathology in animal models of AD. It is noted that Aβ secretion and the expression and activity of β-secretase have been reduced by peroxisome proliferatoractivated receptor-γ [PPAR-γ] agonists and nonsteroidal anti-inflammatory drugs [NSAIDs] [10]. It is suggested that suppression of neuroinflammation with NSAIDs rescues memory and cognitive decline. While retrospective epidemiological studies have proven that prolonged treatment with NSAIDs delays onset of AD when initiated early stage or before disease initiation, its effectiveness has not been demon-

Iron, zinc and copper are important elements for neuronal function. During the aging, these metal ions accumulate in the brain, consequently contribute to neurodegeneration. Zinc, copper and iron have been found to be accumulated within the core and periphery of senile plaques and these metals have been suggested to be involved in Aβ aggregation and oxidative damage. Metal chelation is a therapy based on binding and removing to metal ions. This therapy can provide an advantageous against oxidative stress in AD. Desferrioxamine and clioquinol are several examples of treatment methods with metal chelators. And these methods have caught some success in order to alter the progression of AD [12]. Therapeutic approaches focusing on the improvement of metal balance are one of the popular subjects of current

Mitochondrial dysfunction has a significant function in brain aging and AD. Swerdlow and Kan suggested mitochondrial cascade hypothesis for sporadic form of AD in 2004 [13]. This hypothesis proposes that mitochondrial dysfunction exists early in disease pathogenesis and causes, NFT formation, Aβ deposition and synaptic loss, the mitochondria is vulnerable to oxidative stress because of lack of DNA repair activity and is the significant source of ROS in the central nervous system. Oxidation of mitochondrial DNA presents it vulnerable to somatic mutations which augments mitochondrial dysfunction. Mitochondrial dysfunction has been proposed to trigger onset of neuronal degeneration in AD. It is showed that Aβ accumulates in mitochondria from AD patients. Tau protein might also be included

Type 2 diabetes mellitus is a risk factor for AD and these two disorders share many common pathological pathways. Impaired glucose metabolism is related to rising oxidative stress and accumulated advanced glycation end products. Insulin is even produced in brain tissue itself. Insulin receptors are mostly located in the cerebral cortex, cerebellum, hypothalamus, hippocampus and olfactory bulb that are the cognition pertinent areas of the brain. Brain glucose utilization and insulin signaling are impaired in AD. AD is related to a reduction in the levels of insulin in

#### *Future Treatment of Alzheimer Disease DOI: http://dx.doi.org/10.5772/intechopen.85096*

(COX-2) and proinflammatory cytokines (IL-1β) are boosted in tau-positive nerve cells in spinal cord and brainstem. Pursuant to these results of the research, neuroinflammation might be triggered through NFTs by activating microglia. It is found that suppression of neuroinflammation is related to improvements in behavioral and cognitive deficits in AD mouse models and is in harmony with decline in hyperphosphorylated tau and Aβ plaques in brain. It is efficient to treat with interleukin-1β (IL-1β) antibodies or anti-tumor necrosis factor-α (anti-TNF-α) in order to reduce the pathology in animal models of AD. It is noted that Aβ secretion and the expression and activity of β-secretase have been reduced by peroxisome proliferatoractivated receptor-γ [PPAR-γ] agonists and nonsteroidal anti-inflammatory drugs [NSAIDs] [10]. It is suggested that suppression of neuroinflammation with NSAIDs rescues memory and cognitive decline. While retrospective epidemiological studies have proven that prolonged treatment with NSAIDs delays onset of AD when initiated early stage or before disease initiation, its effectiveness has not been demonstrated in neither mild nor moderate forms of AD [11].
