Tau Pathologies

Tau pathology in AD is circumscribed to neurons, while in other tauopathies, such as corticobasal degeneration, PSP and familial multiple system tauopathy with presenile dementia, both nerve cells and ghal cells are affected (210,211). PINl binds hyperphosphorylated tau, resulting in depletion of soluble PINl in AD brains. 

The intracellular deposition of ABP as the first pathogenic event prior to the appearance of tau pathology in AD (272) is an indirect evidence of ABP aggregation and incapacity of the ubiquitin-proteasome-chaperone system to repair the distorted metabolism of APP-ABP leading to neurodegeneration. A similar phenomenon with aggregation of conformation-abnormal peptides probably plays a key role in many other neurodegenerative disorders. 

Tendon, C.L., Thaker, U., Harris, J.M., et al. (2002) The angiotensin 1-converting enzyme insertion (l)/deletion (D) polymorphism does not influence the extent of amyloid or tau pathology in patients with sporadic Alzheimer s disease. Neurosci. Lett., 328, 314-318. 

Winton M. J., Joyce S., Zhukareva V., Practico D., Perl D. P., Galasko D., Craig U., Trojanowski J. Q., and Lee V. M. (2006). Characterization of tau pathologies in gray and white matter of Guam parkinsonism-dementia complex. Acta Neuropathol. (Berl) 111 401 112. 

Oddo, S., Caccamo, A., Tran, L., Lambert, M. P., Glabe, C. G., Klein, W. L., and LaFerla, F. M. (2006). Temporal profile of amyloid-beta (Abeta) oligomerization in an in vivo model of Alzheimer disease. A link between Abeta and tau pathology. J Biol Chem 281, 1599-1604. 

Both immunohistochemical and biochemical studies indicate that amyloid deposits occur very early in the AD process, preceding the appearance of neocortical neurofibrillary tangles. It should be noted that tau pathology occurs in the form of at least a few tangles, which are almost always restricted to the entorhinal cortex and hippocampus, in many older, nondemented individuals [21]. 

Iqbal, K., Alonso Adel, C., Chen, S., Chohan, M. O., El-Akkad, E., et al. (2005) Tau pathology in Alzheimer disease and other tauopathies. Biochim Biophys Acta 1739, 198-210. 

Tolnay and Probst, 1999). Among the tauopathies, the most studied is AD. The analyses of other types of dementia with tau pathology have usually been performed in comparison with AD (Spillantini and Goedert, 2000). Based on electtophoretic pattern, several classes of tau aggregation are presently described. (1) AD and Parkinsonism dementia complex (six tau isoforms) (2) PSP and CBD (three isoforms with exon 10 corresponding sequence) (3) Pick s disease (PiD) (three isoforms without exon 10), and (4) myotonic dystrophy-the shortest tau isoform (Caparros-Lefebvre et al., 2002). 

Tau pathology corresponds to the intraneuronal aggregation of microtubule-associated tau proteins into abnormal filaments. Paired hehcal filaments (PHF) are the most characteristic cytoskeletal alterations affecting numerous neurons in AD. Using a combined immunocytochemical and biochemical approach (Iqbal et al., 1989) demonshated for the first time that the microtubule-associated protein tau, a normal brain cytoskeletal protein, is a component of the PHF. The authors also indicated for the first time that posttranslational modification of tau such as phosphorylation might occur which would allow it to assemble either alone or together... 

It has been proposed that NFTs are an independent feature accumulating slowly with age within the median temporal lobes. However, under the influence of altered amyloid metabolism, which leads to the formation of Amyloid plaques during the initial stages of the disease, there is an acceleration of NFT formation that spreads further to neocortex (Price and Morris, 2004). However, quantification of Ap in the different brain areas demonstrates that the spreading pathway of tau pathology remains constant, whatever the cortical distribution of A aggregates (Delacourte et al., 2002). In AD brain, tau is abnormally hyperphosphorylated, cleaved, and conformationally changed and is present mostly as PHF (Komori,... 

With all the compelling evidence accumulated thus far, the criteria for AD diagnosis have been revised to include the presence of tau pathology for diagnosing definite AD. 

Morris HR, Baker M, Yasojima K, Houlden H, Khan MN, Wood NW, et al. (2002) Analysis of tau haplotypes in Pick s disease. Neurology 59 443-445 Morris HR, Lees Al, Wood NW (1999) Neurofibrillary tangle parkinsonian disorders-tau pathology and tau genetics. Mov Disord 14 731-736... 

Wszolek ZK, Pfeiffer RF, Tsuboi Y, Uitti RJ, McComb RD, Stoessl AJ, Strongosky AJ, Zimpiich A, Muller-Myhsok B, Farrer MJ, Gasser T, Caine DB, Dickson DW (2004) Autosomal dominant parkinsonism associated with variable synuclein and tau pathology. Neurology 62 1619-1622... 

Arendash GW, Lewis J, Leighty RE, McGowan E, Cracchiolo JR, Hutton M, Garcia ME (2004) Multi-metric behavioral comparison of APPsw and P301L models for Alzheimer s disease Linkage of poorer cognitive performance to tau pathology in forebrain. Brain Res 1012 29-41. 

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