IndraLab

"Finally, because of the high prevalence and early appearance of AD in the DS population and the multiple common mechanisms found in both conditions, DS can be considered a useful model to study AD etiopathology and to search for new therapeutic strategies. [188, 191] ↑ in DS and AD Enhancement of lipid, DNA, and RNA oxidation Glutamatergic system [189, 190] ↑ in AD Promotion of OS-induced excitotoxicity Cholinergic system [191] ↓ in DS and AD Aβ-induced enhancement of OS in cholinergic neurons mTOR [192] [193] [194] 196, 198] ↑ in DS and AD OS disruption of mTOR function and mTOR enhancement of oxidative damage Enhanced oxidative stress [191, 200, 201] ↑ in DS and AD Enhancement of ROS-mediated disruption of mitochondrial integrity and function OXPHOS [203] [204] [205] [206] [209] [210] [211] [212] [213] [214] [215] [216] [217] [218] [219] [220] [221] [222] ↓ in DS and AD Enhancement of Aβ production, alterations in cell membranes and synapses, reduction in mitochondrial inner membrane potential, reduction in energy production, and lower mitochondrial function Raptor/mTOR [197, 223, 224] ↑ in DS and AD Alterations in mitochondrial activity and metabolism Insulin signaling [241] [242] [243] ↓ in DS and AD Alterations in energy metabolism, impairment of neuronal activity, plasticity and survival, and facilitation of Aβ aggregation Glucose transport and metabolism [245] [246] [247] [248] [249] [250] ↓ in DS and AD Reduction in energy for synaptic transmission and neurotransmitter biosynthesis, alterations in autophagy PI3-K/Akt/mTOR [65, 67, [253] [254] [255] [256] ↑ in DS and AD Dysregulation of energy balance, induction of insulin resistance, altered autophagy Release of proinflammatory cytokines [269, 270] ↑ in DS and AD Induction of cellular senescence and enhancement by senescence Oxidative stress and mitochondrial dysfunction [15, 262] ↑ in DS and AD Induction of cellular senescence and enhancement by senescence Proteostasis (Aβ and tau) [267, 268] ↑ in DS and AD Induction of cellular senescence and enhancement by senescence, induction of cellular senescence and enhancement by senescence USP16-Wnt [271] [272] [273] ↑ UPS16 in DS/ ↓ Wnt in DS and AD Induction of senescence through DNA damage, downregulation of the Wnt pathway reducing stem cell renewal p38MAPK [281] [282] [283] [284] [285] ↑ in DS and AD Increase in release of cytokines Aβ/APP [287, 290] ↑ in DS and AD Increase in release of cytokines which further aggravates Aβ pathology HPA [292, 293] ↑ in AD Cytokines produce excessive activation of the HPA, which aggravates the energy deficits and enhances OS Inhibition of proliferation and promotion of premature differentiation, prevention the entry into the S phase of the cycle DYRK1A/Notch [312] [313] [314] Inhibition of notch signaling that controls neurogenesis, induction of a shift from neurogenic to glionenic fate of progenitors DYRK1A/NFAT [316] Delay of neurogenesis by the synergic effect with RCAN1 mTOR [317, 318] ↑ in DS and AD Apoptotic death of NPCs BDNF [92, 322] ↓ in DS and AD Impairment of cell proliferation and differentiation Shh [323] [324] [325] ↓ in DS Impairment of proliferation of NPCs •AD, in individuals with or without DS, is a disease with a complex set of neuropathological signs. •Numerous signalling pathways are implicated in the onset and aggravation of this neuropathology. •The same signalling pathway often plays a role in the appearance or progression of different signs of AD. •In many cases, synergic effects and feedback loops exist between these pathways. •Because of the complex etiopathology of AD and the interrelation between the factors responsible for the symptoms of the disease, therapeutic approaches should combine different targets. • AD, in individuals with or without DS, is a disease with a complex set of neuropathological signs."