Abstract:
BACKGROUND:The microtubule-associated protein tau accumulates in neurodegenerative diseases known as tauopathies, the most common being Alzheimer's disease. One way to treat these disorders may be to reduce abnormal tau levels through chaperone manipulation, thus subverting synaptic plasticity defects caused by tau's toxic accretion. METHODS:Tauopathy models were used to study the impact of YM-01 on tau. YM-01 is an allosteric promoter of triage functions of the most abundant variant of the heat shock protein 70 (Hsp70) family in the brain, heat shock cognate 70 protein (Hsc70). The mechanisms by which YM-01 modified Hsc70 activity and tau stability were evaluated with biochemical methods, cell cultures, and primary neuronal cultures from tau transgenic mice. YM-01 was also administered to acute brain slices of tau mice; changes in tau stability and electrophysiological correlates of learning and memory were measured. RESULTS:Tau levels were rapidly and potently reduced in vitro and ex vivo upon treatment with nanomolar concentrations of YM-01. Consistent with Hsc70 having a key role in this process, overexpression of heat shock protein 40 (DNAJB2), an Hsp70 co-chaperone, suppressed YM-01 activity. In contrast to its effects in pathogenic tauopathy models, YM-01 had little activity in ex vivo brain slices from normal, wild-type mice unless microtubules were disrupted, suggesting that Hsc70 acts preferentially on abnormal pools of free tau. Finally, treatment with YM-01 increased long-term potentiation in tau transgenic brain slices. CONCLUSIONS:Therapeutics that exploit the ability of chaperones to selectively target abnormal tau can rapidly and potently rescue the synaptic dysfunction that occurs in Alzheimer's disease and other tauopathies.
journal_name
Biol Psychiatryjournal_title
Biological psychiatryauthors
Abisambra J,Jinwal UK,Miyata Y,Rogers J,Blair L,Li X,Seguin SP,Wang L,Jin Y,Bacon J,Brady S,Cockman M,Guidi C,Zhang J,Koren J,Young ZT,Atkins CA,Zhang B,Lawson LY,Weeber EJ,Brodsky JL,Gestwicki JE,Dickey CAdoi
10.1016/j.biopsych.2013.02.027subject
Has Abstractpub_date
2013-09-01 00:00:00pages
367-74issue
5eissn
0006-3223issn
1873-2402pii
S0006-3223(13)00225-4journal_volume
74pub_type
杂志文章abstract::Rhesus mother-infant pairs were housed in a playpen apparatus beginning just before the birth of four male infants. The infants were separated from their mothers four times beginning at a mean age of 218 days. In Type A separations (I and IV) the infants were removed and housed away from their familiar environment in ...
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