The amyloid precursor protein APP is a membrane protein thou

The amyloid precursor protein (APP) is a membrane protein thought to be involved in plasticity, synapse formation and repair, and export of metal ions [68]. The APP present in the brain can be cleaved by three different secretases [73], [74]. Cleavage of APP first by alpha secretase and then gamma-secretase results in a functional protein; while cleavage by beta-secretase results in Aβ. The product formed from this improper cleavage – beta amyloid - will aggregate into plaques, and disrupt function of normal cells [19], [74]. These Aβ plaques can be modified by MG and AGEs, forming crosslinks, affording them stability and defense against protease cleavage [75], [76]. Aβ plaques are very stable and have long lives - The progression of AD is preceded 15 years by appearance of Aβ deposits [23], [41] Aβ plaques will disrupt neuron function, and induce ROS production, ultimately leading to inflammation, damage to cell/tissue, and apoptosis [48], [69], [77], [78] Aβ G-15 will clump around neurons and prevent their proper function [67]. The Aβ plaques also attract and activate microglia, causing them to cluster and localize around the plaques [21], [67]. These immune cells release signals inducing cellular toxicity [68]. The Aβ plaques cause additional production of AGEs, which will reduce the activity of enzymes and proteins (especially in mitochondria) [41]. These AGEs will lead to increased ROS production, which increases the production of APP [23], [68]. Aβ plaques can also disrupt redox signaling by interacting with metal ions in active sites of macromolecule, preventing proper function [48]. Impairment of the glyoxalase system can have a direct impact on the severity of AD [22], [73]. Studies have shown glyoxalase I levels decrease with increased aging and severity of AD [14]. The imbalance of antioxidant affects causes a shift to a state of OS. Accumulation of MG and AGEs in the Alzheimer's disease brain is very deleterious [75]. Tissue from AD brain shows high amounts of AGEs and oxidized lipids and proteins, which is a marker of inflammation [41]. There is a correlation with the amount of MG/AGEs localized to specific brain regions and severity of AD [75]. NFT are filaments of bundled proteins formed from a disruption in the microtubule network of cells [67], [74]. Microtubule associated protein tau is responsible for promoting and stabilizing microtubule formation in cells, however hyperphosphorylation of tau destabilizes and disrupts the proper assembly of microtubules [79], [80]. Proteins aggregate and oligomerize forming toxic NFT, causing the death of neurons in the area [81]. Increased MG levels, apoptosis, and OS contribute to production of Aβ and hyperphosphorylation of tau [5]. MG can also disrupt cell signaling pathways that control kinases and phosphatases used to regulate phosphorylation of tau [1], [59] Aβ has an influential and contributing role in the production of NFT, and they are both stable molecules prone to glycation [76]. MG derived AGEs aggregate in NFT and beta amyloid plaques [19]. AGE crosslinking in Aβ affords it insolubility and protease resistance [75], [76]. MG modified Aβ in plaques has a longer half-life, allowing it to accumulate more AGE modifications, which causes more Aβ to form [9], [67]
Parkinson's disease (PD) Parkinson's is the second common neurodegenerative disease. It is characterized by degeneration of dopamine producing neurons in the substantia nigra [19]. This leads to a decrease of dopamine levels in areas of the brain associated with movement, caused by deregulation in ganglion cell circuits [81], [82], [83], [84], [85], [86], [87], [88]. The disease is characterized by motor deficiencies - including tremors, rigidity, and slowness of movement – and cognitive deficiencies [49]. Pathological markers of Parkinson's include the accumulation of alpha synuclein into Lewy bodies [57], [84]. The degeneration of dopaminergic neurons and oxidation of dopamine causes altered mitochondrial respiration, inducing a state of oxidative stress in neural tissue [49], [89]