A Novel Treatment Approach in Alzheimer’s Disease: sAPPα (original) (raw)
Related papers
Cellular and Molecular Life Sciences, 2020
Amyloid precursor protein (APP) is a transmembrane protein expressed largely within the central nervous system. Upon cleavage, it does not produce the toxic amyloid peptide (Aβ) only, which is involved in neurodegenerative progressions but via a non-amyloidogenic pathway it is metabolized to produce a soluble fragment (sAPPα) through α-secretase. While a lot of studies are focusing on the role played by APP in the pathogenesis of Alzheimer's disease, sAPPα is reported to have numerous neuroprotective effects and it is being suggested as a candidate with possible therapeutic potential against Alzheimer's disease. However, the mechanisms through which sAPPα precisely works remain elusive. We have presented a comprehensive review of how sAPPα is regulating the neuroprotective effects in different biological models. Moreover, we have focused on the role of sAPPα during different developmental stages of the brain, neurogenic microenvironment in the brain and how this metabolite of APP is regulating the neurogenesis which is regarded as a compelling approach to ameliorate the impaired learning and memory deficits in dementia and diseases like Alzheimer's disease. sAPPα exerts beneficial physiological, biochemical and behavioral effects mitigating the detrimental effects of neurotoxic compounds. It has shown to increase the proliferation rate of numerous cell types and promised the synaptogenesis, neurite outgrowth, cell survival and cell adhesion. Taken together, we believe that further studies are warranted to investigate the exact mechanism of action so that sAPPα could be developed as a novel therapeutic target against neuronal deficits.
Experimental neurology, 2018
One major pathophysiological hallmark of Alzheimer's disease (AD) is senile plaques composed of amyloid β (Aβ). In the amyloidogenic pathway, cleavage of the amyloid precursor protein (APP) is shifted towards Aβ production and soluble APPβ (sAPPβ) levels. Aβ is known to impair synaptic function; however, much less is known about the physiological functions of sAPPβ. The neurotrophic properties of sAPPα, derived from the non-amyloidogenic pathway of APP cleavage, are well-established, whereas only a few, conflicting studies on sAPPβ exist. The intracellular pathways of sAPPβ are largely unknown. Since sAPPβ is generated alongside Aβ by β-secretase (BACE1) cleavage, we tested the hypothesis that sAPPβ effects differ from sAPPα effects as a neurotrophic factor. We therefore performed a head-to-head comparison of both mammalian recombinant peptides in developing primary hippocampal neurons (PHN). We found that sAPPα significantly increases axon length (p = 0.0002) and that both sAPP...
Journal of neuroscience research, 2016
Soluble amyloid precursor protein α (sAPPα), a secreted proteolytic fragment of nonamyloidogenic amyloid precursor protein (APP) processing, is known for numerous neuroprotective functions. These functions include but are not limited to proliferation, neuroprotection, synaptic plasticity, memory formation, neurogenesis, and neuritogenesis in cell culture and animal models. In addition, sAPPα influences amyloid-β (Aβ) production by direct modulation of APP β-secretase proteolysis as well as Aβ-related or unrelated tau pathology, hallmark pathologies of Alzheimer's disease (AD). Thus, the restoration of sAPPα levels and functions in the brain by increasing nonamyloidogenic APP processing and/or manipulation of its signaling could reduce AD pathology and cognitive impairment. It is likely that identification and characterization of sAPPα receptors in the brain, downstream effectors, and signaling pathways will pave the way for an attractive therapeutic target for AD prevention or i...
Experimental Neurology, 2018
One major pathophysiological hallmark of Alzheimer's disease (AD) is senile plaques composed of amyloid β (Aβ). In the amyloidogenic pathway, cleavage of the amyloid precursor protein (APP) is shifted towards Aβ production and soluble APPβ (sAPPβ) levels. Aβ is known to impair synaptic function; however, much less is known about the physiological functions of sAPPβ. The neurotrophic properties of sAPPα, derived from the non-amyloidogenic pathway of APP cleavage, are well-established, whereas only a few, conflicting studies on sAPPβ exist. The intracellular pathways of sAPPβ are largely unknown. Since sAPPβ is generated alongside Aβ by β-secretase (BACE1) cleavage, we tested the hypothesis that sAPPβ effects differ from sAPPα effects as a neurotrophic factor. We therefore performed a head-to-head comparison of both mammalian recombinant peptides in developing primary hippocampal neurons (PHN). We found that sAPPα significantly increases axon length (p = 0.0002) and that both sAPPα and sAPPβ increase neurite number (p < 0.0001) of PHN at 7 days in culture (DIV7) but not at DIV4. Moreover, both sAPPα-and sAPPβ-treated neurons showed a higher neuritic complexity in Sholl analysis. The number of glutamatergic synapses (p < 0.0001), as well as layer thickness of postsynaptic densities (PSDs), were significantly increased, and GABAergic synapses decreased upon sAPP overexpression in PHN. Furthermore, we showed that sAPPα enhances ERK and CREB1 phosphorylation upon glutamate stimulation at DIV7, but not DIV4 or DIV14. These neurotrophic effects are further associated with increased glutamate sensitivity and CREB1-signaling. Finally, we found that sAPPα levels are significantly reduced in brain homogenates of AD patients compared to control subjects. Taken together, our data indicate critical stage-dependent roles of sAPPs in the developing glutamatergic system in vitro, which might help to understand deleterious consequences of altered APP shedding in AD patients, beyond Aβ pathophysiology.
Neurobiology of Aging, 2017
Amyloid Precursor Protein (APP), key molecule of Alzheimer disease is metabolized in two antagonist pathways generating the sAPPα having neuroprotective properties and the amyloid peptide (Aß) at the origin of neurotoxic oligomers, particularly Aß1-42. Whether extracellular Aß1-42 oligomers modulate the formation and secretion of sAPPα is not known. We report here that the addition of Aß1-42 oligomers to primary cortical neurons induced a transient increase in alpha secretase activity and secreted sAPPα 6-9 h later. Preventing the generation of sAPPα by using siRNAs for the alpha secretases ADAM10 and ADAM17, or for APP led to increased Aß1-42 oligomer-induced cell death after 24 h. Neuronal injuries due to oxidative stress or growth factor deprivation also generated sAPPα 7h later. Finally, acute injection of Aß1-42 oligomers into wild type mouse hippocampi induced transient secretion of sAPPα 48-72 h later. Altogether, these data suggest that neurons respond to stress by generating sAPPα for their survival. These data must be taken into account when interpreting sAPPα levels as a biomarker in neurological disorders.
Hippocampus, 2011
Amyloid precursor protein (APP) is an integral membrane glycoprotein present at high levels in nerve cells. Two soluble secreted forms, sAPPa and sAPPb, are processed from APP by two mutually exclusive proteolytic pathways. sAPPa shows a range of neuroprotective and growth factor properties, including reduction of neuronal injury and improvement in memory performance, in contrast to the generally less potent sAPPb. In addition, sAPPa has been shown to increase the proliferation of both embryonic neural stem cells and neural progenitor cells (NPCs) derived from the subventricular zone (SVZ) of the adult brain. However, an effect of sAPPa (or sAPPb) on adult hippocampal progenitor cell proliferation and differentiation has not previously been observed. In this study, we examined the effect of both the aand b-cleaved ectodomains of sAPP on adult NPCs isolated from the subgranular zone (SGZ) of the rat hippocampus in the presence or absence of depolarizing conditions. Assays were performed to examine the effect of sAPPa and sAPPb on SGZ-derived adult NPC proliferation in parallel with SVZ-derived cells and on differentiation with SGZ-derived cells. We observed both sAPPa and sAPPb increased the proliferation of SGZderived NPCs in vitro. Further, treatment of SGZ-derived NPCs with either sAPPa or sAPPb increased the number of cells expressing the astrocytic marker GFAP and promoted cell survival. The effect on differential fate was observed in both the presence and absence of depolarizing conditions. Thus, both sAPPa and sAPPb exert a complex range of effects on SGZ-derived adult NPCs, including increasing NPC proliferation, maintaining cell viability, yet promoting glial over neuronal differentiation. These findings provide the first direct support for the secreted forms of APP regulating SGZ-derived NPCs, and raise the possibility some or all of the effects may have therapeutic benefit in models of neurological disease. V
Roles of amyloid precursor protein family members in neuroprotection, stress signaling and aging
Experimental Brain Research, 2011
The roles of amyloid precursor protein (APP) family members in normal brain function are poorly understood. Under physiological conditions the majority of APP appears to be processed along the non-amyloidogenic pathway leading to the formation of the secreted N-terminal APP fragment sAPPa. This cleavage product of APP has been implicated in several physiological processes such as neuroprotection, synaptic plasticity, neurite outgrowth and synaptogenesis. In this review we focus on the role of APP family members in neuroprotection and summarize the cellular and molecular mechanisms which are believed to mediate this effect. We propose that a reduction of APP processing along the non-amyloidogenic pathway during brain aging could result in an enhanced susceptibility of neurons to cellular stress and could contribute to neurodegeneration in Alzheimer's disease.