Argyrophilic grain disease differs from other tauopathies by lacking tau acetylation.
Post-translational modifications play a key role in tau protein aggregation and related neurodegeneration. Because hyperphosphorylation alone does not necessarily cause tau aggregation, other post-translational modifications have been recently explored. Tau acetylation promotes aggregation and inhibits tau's ability to stabilize microtubules. Recent studies have shown co-localization of acetylated and phosphorylated tau in AD and some 4R tauopathies. We developed a novel monoclonal antibody against acetylated tau at lysine residue 274, which recognizes both 3R and 4R tau, and used immunohistochemistry and immunofluorescence to probe 22 cases, including AD and another eight familial or sporadic tauopathies. Acetylated tau was identified in all tauopathies except argyrophilic grain disease (AGD). AGD is an age-associated, common but atypical 4R tauopathy, not always associated with clinical progression. Pathologically, AGD is characterized by neuropil grains, pre-neurofibrillary tangles, and oligodendroglial coiled bodies, all recognized by phospho-tau antibodies. The lack of acetylated tau in these inclusions suggests that AGD represents a distinctive tauopathy. Our data converge with previous findings to raise the hypothesis that AGD could play a protective role against the spread of AD-related tau pathology. Tau acetylation as a key modification for the propagation tau toxicity deserves further investigation.
Memory and Aging Center, Department of Neurology University of California, San Francisco, 675 Nelson Rising Lane, San Francisco, CA 94158, USA.
Lea Tenenholz
LT
Grinberg
Xuehua
X
Wang
Chao
C
Wang
Peter Dongmin
PD
Sohn
Panos
P
Theofilas
Manu
M
Sidhu
John Benjamin
JB
Arevalo
Helmut
H
Heinsen
Eric J
EJ
Huang
Howard
H
Rosen
Bruce L
BL
Miller
Li
L
Gan
William W
WW
Seeley
D000107:Acetylation; D000368:Aged; D000369:Aged, 80 and over; D001921:Brain / Q000378:metabolism* / Q000473:pathology; D003937:Diagnosis, Differential; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D016874:Neurofibrillary Tangles / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D058225:Plaque, Amyloid / Q000378:metabolism / Q000473:pathology; D011499:Protein Processing, Post-Translational; D024801:Tauopathies / Q000175:diagnosis* / Q000378:metabolism / Q000473:pathology; D016875:tau Proteins / Q000378:metabolism*
D016875:tau Proteins