Amyloid-independent Mechanisms in Alzheimer's Disease Pathogenesis

Overview

Journal J Neurosci

Specialty Neurology

Date 2010 Nov 12

PMID 21068297

Citations 137

Authors

Sanjay W Pimplikar

Ralph A Nixon

Nikolaos K Robakis

Jie Shen

Li-Huei Tsai

Affiliations

Soon will be listed here.

Abstract

Despite the progress of the past two decades, the cause of Alzheimer's disease (AD) and effective treatments against it remain elusive. The hypothesis that amyloid-β (Aβ) peptides are the primary causative agents of AD retains significant support among researchers. Nonetheless, a growing body of evidence shows that Aβ peptides are unlikely to be the sole factor in AD etiology. Evidence that Aβ/amyloid-independent factors, including the actions of AD-related genes, also contribute significantly to AD pathogenesis was presented in a symposium at the 2010 Annual Meeting of the Society for Neuroscience. Here we summarize the studies showing how amyloid-independent mechanisms cause defective endo-lysosomal trafficking, altered intracellular signaling cascades, or impaired neurotransmitter release and contribute to synaptic dysfunction and/or neurodegeneration, leading to dementia in AD. A view of AD pathogenesis that encompasses both the amyloid-dependent and -independent mechanisms will help fill the gaps in our knowledge and reconcile the findings that cannot be explained solely by the amyloid hypothesis.

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References

Cataldo A, Peterhoff C, Troncoso J, Gomez-Isla T, Hyman B, Nixon R . Endocytic pathway abnormalities precede amyloid beta deposition in sporadic Alzheimer's disease and Down syndrome: differential effects of APOE genotype and presenilin mutations. Am J Pathol. 2000; 157(1):277-86. PMC: 1850219. DOI: 10.1016/s0002-9440(10)64538-5. View

Rothenberg C, Srinivasan D, Mah L, Kaushik S, Peterhoff C, Ugolino J . Ubiquilin functions in autophagy and is degraded by chaperone-mediated autophagy. Hum Mol Genet. 2010; 19(16):3219-32. PMC: 2908472. DOI: 10.1093/hmg/ddq231. View

Garcia-Arencibia M, Hochfeld W, Toh P, Rubinsztein D . Autophagy, a guardian against neurodegeneration. Semin Cell Dev Biol. 2010; 21(7):691-8. PMC: 2938570. DOI: 10.1016/j.semcdb.2010.02.008. View

Watanabe H, Smith M, Heilig E, Beglopoulos V, Kelleher 3rd R, Shen J . Indirect regulation of presenilins in CREB-mediated transcription. J Biol Chem. 2009; 284(20):13705-13713. PMC: 2679472. DOI: 10.1074/jbc.M809168200. View

Li Y, Rinne J, Mosconi L, Pirraglia E, Rusinek H, DeSanti S . Regional analysis of FDG and PIB-PET images in normal aging, mild cognitive impairment, and Alzheimer's disease. Eur J Nucl Med Mol Imaging. 2008; 35(12):2169-81. PMC: 2693402. DOI: 10.1007/s00259-008-0833-y. View

Georgakopoulos A, Litterst C, Ghersi E, Baki L, Xu C, Serban G . Metalloproteinase/Presenilin1 processing of ephrinB regulates EphB-induced Src phosphorylation and signaling. EMBO J. 2006; 25(6):1242-52. PMC: 1422162. DOI: 10.1038/sj.emboj.7601031. View

Baki L, Neve R, Shao Z, Shioi J, Georgakopoulos A, Robakis N . Wild-type but not FAD mutant presenilin-1 prevents neuronal degeneration by promoting phosphatidylinositol 3-kinase neuroprotective signaling. J Neurosci. 2008; 28(2):483-90. PMC: 6670519. DOI: 10.1523/JNEUROSCI.4067-07.2008. View

Spilman P, Podlutskaya N, Hart M, Debnath J, Gorostiza O, Bredesen D . Inhibition of mTOR by rapamycin abolishes cognitive deficits and reduces amyloid-beta levels in a mouse model of Alzheimer's disease. PLoS One. 2010; 5(4):e9979. PMC: 2848616. DOI: 10.1371/journal.pone.0009979. View

Stiegler P, De Luca A, Bagella L, Giordano A . The COOH-terminal region of pRb2/p130 binds to histone deacetylase 1 (HDAC1), enhancing transcriptional repression of the E2F-dependent cyclin A promoter. Cancer Res. 1998; 58(22):5049-52. View

10.

Jiang Y, Mullaney K, Peterhoff C, Che S, Schmidt S, Boyer-Boiteau A . Alzheimer's-related endosome dysfunction in Down syndrome is Abeta-independent but requires APP and is reversed by BACE-1 inhibition. Proc Natl Acad Sci U S A. 2010; 107(4):1630-5. PMC: 2824382. DOI: 10.1073/pnas.0908953107. View

11.

Ohmi K, Kudo L, Ryazantsev S, Zhao H, Karsten S, Neufeld E . Sanfilippo syndrome type B, a lysosomal storage disease, is also a tauopathy. Proc Natl Acad Sci U S A. 2009; 106(20):8332-7. PMC: 2677546. DOI: 10.1073/pnas.0903223106. View

12.

Choi S, Park C, Koo J, Seo J, Kim H, Jeong S . Memory impairment and cholinergic dysfunction by centrally administered Abeta and carboxyl-terminal fragment of Alzheimer's APP in mice. FASEB J. 2001; 15(10):1816-8. DOI: 10.1096/fj.00-0859fje. View

13.

Cataldo A, Petanceska S, Peterhoff C, Terio N, Epstein C, Villar A . App gene dosage modulates endosomal abnormalities of Alzheimer's disease in a segmental trisomy 16 mouse model of down syndrome. J Neurosci. 2003; 23(17):6788-92. PMC: 6740714. View

14.

Lee K, Im J, Song J, Lee S, Lee H, Ha H . Progressive neuronal loss and behavioral impairments of transgenic C57BL/6 inbred mice expressing the carboxy terminus of amyloid precursor protein. Neurobiol Dis. 2005; 22(1):10-24. DOI: 10.1016/j.nbd.2005.09.011. View

15.

Ghosal K, Vogt D, Liang M, Shen Y, Lamb B, Pimplikar S . Alzheimer's disease-like pathological features in transgenic mice expressing the APP intracellular domain. Proc Natl Acad Sci U S A. 2009; 106(43):18367-72. PMC: 2762847. DOI: 10.1073/pnas.0907652106. View

16.

Sun B, Zhou Y, Halabisky B, Lo I, Cho S, Mueller-Steiner S . Cystatin C-cathepsin B axis regulates amyloid beta levels and associated neuronal deficits in an animal model of Alzheimer's disease. Neuron. 2008; 60(2):247-57. PMC: 2755563. DOI: 10.1016/j.neuron.2008.10.001. View

17.

Masliah E, Mallory M, Deerinck T, DeTeresa R, Lamont S, Miller A . Re-evaluation of the structural organization of neuritic plaques in Alzheimer's disease. J Neuropathol Exp Neurol. 1993; 52(6):619-32. DOI: 10.1097/00005072-199311000-00009. View

18.

Shen J, Kelleher 3rd R . The presenilin hypothesis of Alzheimer's disease: evidence for a loss-of-function pathogenic mechanism. Proc Natl Acad Sci U S A. 2007; 104(2):403-9. PMC: 1766397. DOI: 10.1073/pnas.0608332104. View

19.

Boland B, Kumar A, Lee S, Platt F, Wegiel J, Yu W . Autophagy induction and autophagosome clearance in neurons: relationship to autophagic pathology in Alzheimer's disease. J Neurosci. 2008; 28(27):6926-37. PMC: 2676733. DOI: 10.1523/JNEUROSCI.0800-08.2008. View

20.

Kim D, Frank C, Dobbin M, Tsunemoto R, Tu W, Peng P . Deregulation of HDAC1 by p25/Cdk5 in neurotoxicity. Neuron. 2008; 60(5):803-17. PMC: 2912147. DOI: 10.1016/j.neuron.2008.10.015. View