**2.3 Metal toxicity**

*Geriatric Medicine and Gerontology*

isolated from AD brain in the 1990s [5].

**2.1 Oxidative stress**

changes observed in AD [7].

**2.2 Neuroinflammation**

phorylation have not been exactly clarified yet.

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

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

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 hyperphos-

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

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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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 researches in the field of AD.
