New therapeutic targets for the treatment of Alzheimer’s disease – Novel insight from transgenic models

Alzheimer’s disease (AD) is the most common neurodegenerative disorder and is generally recognized as the leading cause of dementia as well as one of the main causes of death. Recently it has been estimated that there are more than 46,8 million people worldwide affected by dementia. Since the worldwide numbers of older people as well as the average life expectancy are increasing, the prevalence of chronic diseases like AD and other kind of dementia are destined to increase dramatically in the next years. In particular, it has been calculated that this number will increase in the next twenty years, reaching 74.7 million in 2030 and 131.5 million in 2050. From an economic point of view, another serious challenge that must be overcome is the growing demand for medical assistance and caregivers as well as the unsustainable growth of the socio-economic costs derived from AD pathology. AD is characterized by a progressive impairment of cognitive functions, such as attention, memory, learning, language, motor-perceptive ability, executive functions and social cognition. Moreover AD patients are also affected by non-cognitive and neuropsychiatric symptoms, such as depression, apathy and psychosis. There are two known forms of AD: the sporadic form, which represent the majority of AD cases (95%) and is characterized by an unknown aetiology, and the familial form, the most rare form of AD, which is caused by mutations in one of three genes, presenilin 1 (PSEN1), presenilin 2 (PSEN2) and amyloid precursor protein (APP). The main neuropathological lesions observed in the brains of AD patients are the formation of extracellular neuritic plaques, formed mainly by amyloid-β peptide (Aβ), as well as the intraneuronal formation of neurofibrillary tangles (NFTs), formed mainly by the accumulation of hyperphosphorylated Tau proteins. Currently the main mechanisms involved in AD pathogenesis have been extensively studied, and the major hypothesis supported by the scientific community is the “amyloid cascade hypothesis”, which suggests that AD is caused by an increased expression and an impaired clearance of Aβ. To this regard is widely accepted that Aβ and Tau aggregates are cytotoxic and can interfere with the normal vital processes of the brain cells. In fact the accumulation of these unfolded proteins can cause direct injury to neurons, leading to oxidative stress, neuroinflammation, synaptic dysfunctions, neuronal loss, astrocytosis, gliosis and a marked atrophy of the affected brain regions. Although the amyloid hypothesis is widely accepted, the molecular pathways that link Aβ accumulation with cognitive impairment as well as with the triggering of tau pathology has yet to be clarified. Currently, there are no definitive and effective cares that are able to prevent, block or just slow down the onset and the progression of AD. To date, the main Alzheimer’s drugs available on the market are just able to offers little benefits to patients but often these treatments are accompanied by several side effects. Drug discovery and development processes for AD are long and arduous. The last approved drug for the treatment of AD was memantine and dates back to 2002 in Europe and 2003 in USA. On the bases of these premises, it’s growing the interest in the discovery and identification of novel therapeutic targets for the development of new promising drugs for the treatment of AD. In this study we evaluated a new potential therapeutic strategy for the treatment of AD based on the use of three different molecular targets, which include the mammalian target of Rapamicyne (mTOR), the fatty acid amide hydrolase (FAAH) and the 51 kDa FK506-binding protein (FKBP51). In the following paragraphs the rationale behind the choice of these molecular targets will be explained in detail.