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SAGE KE Bulletin Board

Comment on Saito et al. Nat Med 11: 434-439

5 May 2005

Dietmar R. Thal

Comment on Saito et al. Somatostatin regulates brain amyloid beta peptide Abeta42 through modulation of proteolytic degradation. Nat Med 11: 434-439

Alzheimer's disease (AD) is associated with an increase of the soluble amyloid beta-peptide (Abeta)-levels in the brain as well as with the deposition of Abeta. For sporadic AD, it is suggested that the alteration of clearance mechanisms for Abeta plays an important role for the increase of soluble forms of Abeta and its deposition. The article of Saito et al. demonstrates that an age related downregulation of somatostatin expression is responsible for the downregulation of the neprilysin-related clearance of Abeta. This report indicates that the regulation of clearance pathways potentially leads to the development of sporadic late-onset AD. Moreover, regulation of Abeta clearance mechanisms becomes of pharmacological interest for the treatment of late-onset AD. In the light of the finding of Saito et al. (1) it is important to note that alterations of other clearance mechanisms such as an apolipoprotein E -dependent atroglial uptake of Abeta (2), microglial Abeta uptake following immunization (3) or the clearance along the perivascular spaces (4) may also contribute significantly to the increase of soluble Abeta levels and the deposition of Abeta. Morphological correlates for astroglial Abeta uptake (5-7) as well as for the alteration of the vessel wall of cerebral small vessels in AD (4, 8-11) are well known pathological features of sporadic late-onset AD. To sufficiently reduce the Abeta-load a simultaneous improvement of all altered physiological clearance pathways may be required for the treatment of sporadic AD.

References:

1. Saito T, Iwata N, Tsubuki S, et al. (2005) Somatostatin regulates brain amyloid beta peptide Abeta(42) through modulation of proteolytic degradation. Nat Med 11: 434-439.
2. Koistinaho M, Lin S, Wu X, et al. (2004) Apolipoprotein E promotes astrocyte colocalization and degradation of deposited amyloid-beta peptides. Nat Med 10: 719-726.
3. Schenk D, Barbour R, Dunn W, et al. (1999) Immunization with amyloid- beta attenuates Alzheimer-disease-like pathology in the PDAPP mouse. Nature 400: 173-177.
4. Weller RO, Massey A, Newman TA, Hutchings M, Kuo YM, Roher AE. (1998) Cerebral amyloid angiopathy: amyloid beta accumulates in putative interstitial fluid drainage pathways in Alzheimer's disease. Am J Pathol 153: 725-733.
5. Funato H, Yoshimura M, Yamazaki T, et al. (1998) Astrocytes containing amyloid beta-protein (Abeta)-positive granules are associated with Abeta40 -positive diffuse plaques in the aged human brain. Am J Pathol 152: 983- 992.
6. Thal DR, Schultz C, Dehghani F, Yamaguchi H, Braak H, Braak E. (2000) Amyloid beta-protein (Abeta)-containing astrocytes are located preferentially near N-terminal-truncated Abeta deposits in the human entorhinal cortex. Acta Neuropathol (Berl) 100: 608-617.
7. Yamaguchi H, Sugihara S, Ogawa A, Saido TC, Ihara Y. (1998) Diffuse plaques associated with astroglial amyloid beta protein, possibly showing a disappearing stage of senile plaques. Acta Neuropathol (Berl) 95: 217- 222.
8. Jellinger KA. (2002) Alzheimer disease and cerebrovascular pathology: an update. J Neural Transm 109: 813-836.
9. Kalaria RN, Ballard C. (1999) Overlap between pathology of Alzheimer disease and vascular dementia. Alzheimer Dis Assoc Disord 13 Suppl 3: S115 -123.
10. Skoog I, Kalaria RN, Breteler MM. (1999) Vascular factors and Alzheimer disease. Alzheimer Dis Assoc Disord 13 Suppl 3: S106-114.
11. Thal DR, Ghebremedhin E, Orantes M, Wiestler OD. (2003) Vascular pathology in Alzheimer's disease: Correlation of cerebral amyloid angiopathy and arteriosclerosis / lipohyalinosis with cognitive decline. J Neuropathol Exp Neurol 62: 1287-1301.


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