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br Introduction Alzheimer s disease AD is a neurodegenerativ
Introduction
Alzheimer's disease (AD) is a neurodegenerative disorder and the leading cause of dementia. It is characterized by progressive and irreversible damage to different Cy3-dCTP areas, resulting in cognitive impairment and behavioral changes (O'Neill, 2013, De Strooper and Karran, 2016, Alzheimer's Association, 2017). In 2015, over 47 million people lived with dementia worldwide, and it is estimated that this number will increase to more than 131 million by 2050. The rising incidence of AD is connected to an increase in world’s population life expectancy and changes in population habits. These data indicate this pathological condition as an important global health issue (Subramaniam et al., 2015, Prince et al., 2016).
The main neuropathological feature of AD is believed to be the abnormal protein accumulation. There is an increase in the amyloid precursor protein (APP) amyloidogenic processing by β and γ-secretases, instead of the non-amyloidogenic processing by α and γ-secretases, leading to an overproduction of amyloid-β (Aβ) peptides, specially the Aβ 1–40 and 1–42 residues. Aβ accumulates both in a soluble and an insoluble form, which form the senile plaques (Grimm et al., 2013, Jiang et al., 2014, Robinson et al., 2014, Lazzari et al., 2015). Furthermore, hyperphosphorylation of the tau protein, which induces the formation of aberrant structures and loss of its function, leads to its aggregation and accumulation as neurofibrillary tangles (NFTs) in the CNS (Serrano-Pozo et al., 2011, Mokhtar et al., 2013).
Several risk factors for the development of AD have been listed, including smoking, diabetes mellitus, hypertension and others (Qiu et al., 2005, Biessels et al., 2006, Anstey et al., 2007). Moreover, dyslipidemia and inflammation were recently indicated as risk factors for AD. Mutations in several genes involved in cholesterol metabolism or transport are linked to an increased risk for AD, and cell biology studies show that lipid raft cholesterol is involved in APP processing (Reitz, 2013). Studies have shown that immune response, especially involving innate immune cells, is not only a secondary event to the peptide deposition in the brain, but also plays an important part in AD pathogenesis (Bradshaw et al., 2013, Jonsson et al., 2013).
Dyslipidemia in AD
Dyslipidemias are disorders in which abnormal levels of lipids and/or lipoproteins are found in the blood, which comprises increased cholesterol and/or triglyceride levels. Genetic factors are among the main events involved in the development of dyslipidemias. In fact, hypercholesterolemia is strongly associated with mutations in genes encoding proteins involved in cholesterol metabolism, such as low-density lipoprotein receptor (LDLR) and proprotein convertase subtilisin-like kexin type 9 (PCSK9) (Patni et al., 2000, Waite et al., 2016, Chang and Robidoux, 2017).
Lipids have important functions in several biological events, such as cell-signaling pathways, and are crucial in cell structure organization (Yin et al., 2015). In the brain, the blood–brain barrier (BBB) isolates cholesterol biogenesis from that of the rest of the body. This process occurs especially in neurons and astrocytes, where enzymes convert different intermediate molecules during cholesterol biogenesis (Zhang and Liu, 2015). During the early stages of development, however, oligodendrocytes synthesize large amounts of cholesterol, necessary for myelination (Dietschy and Turley, 2004), when the peak of CNS cholesterol production occurs. Once this process is finished, cholesterol production becomes basal in order to maintain the turnover (Morell and Jurevics, 1996). Similar to cholesterol, the metabolism of lipoproteins in the CNS is independent from the periphery. Glial cells, mainly astrocytes, are the main sources of lipoproteins in the CNS (Dietschy and Turley, 2004). Cholesterol can be processed by CYP46A1 to 24-hydroxycholesterol (24-HC), which can cross the BBB and bind to low-density lipoprotein (LDL) or high-density lipoprotein (HDL). Cholesterol flux across the BBB is also possible via ATP-binding cassette transporters (ABC) and neuronal and scavenger receptors (Petrov et al., 2016).