The Presenilins in Alzheimer's Disease--Proteolysis Holds the Key
Adolf-Butenandt-Institute, Department of Biochemistry, Ludwig-Maximilians University Munich, Germany. Science
(Impact Factor: 33.61).
11/1999; 286(5441):916-9. DOI: 10.1126/science.286.5441.916
Alzheimer's disease (AD) research has shown that patients with an inherited form of the disease carry mutations in the presenilin proteins or the amyloid precursor protein (APP). These disease-linked mutations result in increased production of the longer form of amyloid-beta (the primary component of the amyloid deposits found in AD brains). However, it is not clear how the presenilins contribute to this increase. New findings now show that the presenilins affect APP processing through their effects on gamma-secretase, an enzyme that cleaves APP. Also, it is known that the presenilins are involved in the cleavage of the Notch receptor, hinting that they either directly regulate gamma-secretase activity or themselves are protease enzymes. These findings suggest that the presenilins may prove to be valuable molecular targets for the development of drugs to combat AD.
Available from: PubMed Central
- "In particular, the signaling receptors, which are the substrates of the γ–secretase complex, represent a synaptic hub (De Strooper and Annaert, 2001; Parks and Curtis, 2007) and are implicated in the memory deficit associated with Alzheimer's disease (AD; Haass and De Strooper, 1999; De Strooper et al., 2012). Notch and Reelin signaling, which are both under γ–secretase's regulation, functionally converge in mediating cortical migration and dendritic patterning (Gaiano, 2008; Hashimoto-Torii et al., 2008). "
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ABSTRACT: Notch signaling plays a crucial role in adult brain function such as synaptic plasticity, memory and olfaction. Several reports suggest an involvement of this pathway in neurodegenerative dementia. Yet, to date, the mechanism underlying Notch activity in mature neurons remains unresolved. In this work, we investigate how Notch regulates synaptic potentiation and contributes to the establishment of memory in mice. We observe that Notch1 is a postsynaptic receptor with functional interactions with the Reelin receptor, apolipoprotein E receptor 2 (ApoER2) and the ionotropic receptor, N-methyl-D-aspartate receptor (NMDAR). Targeted loss of Notch1 in the hippocampal CA fields affects Reelin signaling by influencing Dab1 expression and impairs the synaptic potentiation achieved through Reelin stimulation. Further analysis indicates that loss of Notch1 affects the expression and composition of the NMDAR but not AMPAR. Glutamatergic signaling is further compromised through downregulation of CamKII and its secondary and tertiary messengers resulting in reduced cAMP response element-binding (CREB) signaling. Our results identify Notch1 as an important regulator of mechanisms involved in synaptic plasticity and memory formation. These findings emphasize the possible involvement of this signaling receptor in dementia.
In this paper, we propose a mechanism for Notch1-dependent plasticity that likely underlies the function of Notch1 in memory formation:
Notch1 interacts with another important developmental pathway, the Reelin cascade.
Notch1 regulates both NMDAR expression and composition.
Notch1 influences a cascade of cellular events culminating in CREB activation.
Available from: Gerard Griffioen
- "In addition, APP, its processing machinery , and the AICD impact signalling independent of Aí µí»½ formation (reviewed in ). For instance, PS1, a subunit of the í µí»¾-secretase complex, cleaves numerous transmembrane signalling receptors and transducers other than APP CTFs, including Notch, cadherins, ErbB4, LDL receptor related proteins, and so forth  . In addition, PS1 and PS2 impact signalling pathways directly. "
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ABSTRACT: Although a wide variety of genetic and nongenetic Alzheimer's disease (AD) risk factors have been identified, their role in onset and/or progression of neuronal degeneration remains elusive. Systematic analysis of AD risk factors revealed that perturbations of intraneuronal signalling pathways comprise a common mechanistic denominator in both familial and sporadic AD and that such alterations lead to increases in Aβ oligomers (Aβo) formation and phosphorylation of TAU. Conversely, Aβo and TAU impact intracellular signalling directly. This feature entails binding of Aβo to membrane receptors, whereas TAU functionally interacts with downstream transducers. Accordingly, we postulate a positive feedback mechanism in which AD risk factors or genes trigger perturbations of intraneuronal signalling leading to enhanced Aβo formation and TAU phosphorylation which in turn further derange signalling. Ultimately intraneuronal signalling becomes deregulated to the extent that neuronal function and survival cannot be sustained, whereas the resulting elevated levels of amyloidogenic Aβo and phosphorylated TAU species self-polymerizes into the AD plaques and tangles, respectively.
Available from: Xian Zhang
- "BACE1-digested APP CTFs are subsequently cleaved by the γ-secretase complex to release Aβ. In addition, γ-secretase cleaves a series of functionally important substrates such as NOTCH  and tyrosinase . γ-secretase activity is produced from a high molecular weight complex consisting of at least four transmembrane components: presenilin (PS, with two mammalian homologs as PS1 and PS2), nicastrin, anterior pharynx-defective-1 (APH-1), and presenilin enhancer-2 (PEN2) [140,141]. "
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ABSTRACT: The beta-amyloid (Abeta) peptide has been postulated to be a key determinant in the pathogenesis of Alzheimer's disease (AD). Abeta is produced through sequential cleavage of the beta-amyloid precursor protein (APP) by beta- and gamma-secretases. APP and relevant secretases are transmembrane proteins and traffic through the secretory pathway in a highly regulated fashion. Perturbation of their intracellular trafficking may affect dynamic interactions among these proteins, thus altering Abeta generation and accelerating disease pathogenesis. Herein, we review recent progress elucidating the regulation of intracellular trafficking of these essential protein components in AD.
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