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Berman DE, Dall'armi C, Voronov SV, McIntire LB, Zhang H, Moore AZ, Staniszewski A, Arancio O, Kim TW, Di Paolo G. Oligomeric amyloid-beta peptide disrupts phosphatidylinositol-4,5-bisphosphate metabolism. Nat Neurosci. 2008 May;11(5):547-54. PubMed.
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Institute for Brain Aging & Dementia
In an elegant series of studies, one mechanism through which Aβ oligomers may cause synaptic dysfunction may be disruption in phophatidylinositol-4,5-bisphosphate (PtdIns(4,5)P2 ) metabolism. The authors show that oligomeric Aβ destabilizes and reduces PtdIns(4,5)P2 in a pathway that involves extracellular calcium and requires intact function of NMDA. PtdIns(4,5)P2 is consumed after exposure to Aβ oligomers through two pathways involving PLC and synaptojanin 1. Further, mice haplo-deficient for synaptojanin-1, a protein critically involved with synaptic vesicle cycling and a key PtdIns(4,5)P2 phosphatase, were protected from Aβ oligomer toxicity.
As the authors indicate, the results of their study are very interesting in light of the overexpression of synaptojanin 1 in trisomy 21/Down syndrome (DS). Individuals with DS begin developing Aβ deposits in their early thirties (although there have been reports of individuals younger than this being affected), and full blown AD pathology in their forties (Mann and Esiri, 1989). Interestingly, the development of dementia in this cohort begins to rise when adults reach their fifties (Lai, 1989). If synaptojanin 1 is overexpressed in DS, it may be another contributing factor to the early age of onset of AD in DS.
There may be another interesting aspect to the synaptojanin 1 story in DS. As would be predicted, synaptojanin 1 protein levels are higher in DS relative to age-matched controls both in adult and fetal brain (Arai et al., 2002; Cheon et al., 2003). Other genes on chromosome 21 may further exacerbate the interaction between Aβ oligomers and phosphoinositide-mediated synaptic dysfunction. Synaptojanin 1 is phosphorylated by Minibrain kinase/dual specificity tyrosine-phosphorylation regulated kinase 1A (Mnb/Dyrk1A), which is also on chromosome 21 and over-expressed in DS (Adayev et al., 2006). Further, synaptojanin 1 phosphorylation by MNB/Dyrk1A leads to a small but measurable increase in the hydrolysis of PI(4,5)P2 (Adayev et al., 2006). Interestingly, there is a 27 percent reduction in total phospholipids in DS brain (Murphy et al., 2000) including a 37 percent reduction in phosphatidylinositol in the frontal cortex, an area that is vulnerable to Aβ pathology.
Although phosphorylation of synaptojanin 1 by MNB/Dryk1A may generate only a small enhancement of PI15ase activity (Adayev et al., 2006), combined with overexpression of APP and potential generation of Aβ oligomers this may substantially increase synaptic dysfunction and leave neurons particularly vulnerable to additional AD pathology. In combination, the work by Berman and colleagues provides intriguing new insights into the factors leading to AD pathogenesis in DS.
References:
Adayev T, Chen-Hwang MC, Murakami N, Wang R, Hwang YW. MNB/DYRK1A phosphorylation regulates the interactions of synaptojanin 1 with endocytic accessory proteins. Biochem Biophys Res Commun. 2006 Dec 29;351(4):1060-5. PubMed.
Arai Y, Ijuin T, Takenawa T, Becker LE, Takashima S. Excessive expression of synaptojanin in brains with Down syndrome. Brain Dev. 2002 Mar;24(2):67-72. PubMed.
Cheon MS, Kim SH, Ovod V, Kopitar Jerala N, Morgan JI, Hatefi Y, Ijuin T, Takenawa T, Lubec G. Protein levels of genes encoded on chromosome 21 in fetal Down syndrome brain: challenging the gene dosage effect hypothesis (Part III). Amino Acids. 2003;24(1-2):127-34. PubMed.
Lai F, Williams RS. A prospective study of Alzheimer disease in Down syndrome. Arch Neurol. 1989 Aug;46(8):849-53. PubMed.
Mann DM, Esiri MM. The pattern of acquisition of plaques and tangles in the brains of patients under 50 years of age with Down's syndrome. J Neurol Sci. 1989 Feb;89(2-3):169-79. PubMed.
Murphy EJ, Schapiro MB, Rapoport SI, Shetty HU. Phospholipid composition and levels are altered in Down syndrome brain. Brain Res. 2000 Jun 9;867(1-2):9-18. PubMed.
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