Tau reduction prevents Aß-induced axonal transport deficits by blocking activation of GSK3ß.

Axonal transport deficits in Alzheimer's disease (AD) are attributed to amyloid ß (Aß) peptides and pathological forms of the microtubule-associated protein tau. Genetic ablation of tau prevents neuronal overexcitation and axonal transport deficits caused by recombinant Aß oligomers. Relevance of these findings to naturally secreted Aß and mechanisms underlying tau's enabling effect are unknown. Here we demonstrate deficits in anterograde axonal transport of mitochondria in primary neurons from transgenic mice expressing familial AD-linked forms of human amyloid precursor protein. We show that these deficits depend on Aß1-42 production and are prevented by tau reduction. The copathogenic effect of tau did not depend on its microtubule binding, interactions with Fyn, or potential role in neuronal development. Inhibition of neuronal activity, N-methyl-d-aspartate receptor function, or glycogen synthase kinase 3ß (GSK3ß) activity or expression also abolished Aß-induced transport deficits. Tau ablation prevented Aß-induced GSK3ß activation. Thus, tau allows Aß oligomers to inhibit axonal transport through activation of GSK3ß, possibly by facilitating aberrant neuronal activity.

On the positive and negative affective responses to cocaine and their relation to drug self-administration in rats.

RATIONALE: Acute cocaine administration produces an initial rewarding state followed by a dysphoric/anxiogenic "crash." OBJECTIVE: The objective of this study was to determine whether individual differences in the relative value of cocaine's positive and negative effects would account for variations in subsequent drug self-administration. METHODS: The dual actions of cocaine were assessed using a conditioned place test (where animals formed preferences for environments paired with the immediate rewarding effects of 1.0mg/kg i.v. cocaine or aversions of environments associated with the anxiogenic effects present 15-min postinjection) and a runway test (where animals developed approach-avoidance "retreat" behaviors about entering a goal box associated with cocaine delivery). Ranked scores from these two tests were then correlated with each other and with the escalation in the operant responding of the same subjects observed over 10 days of 1- or 6-h/day access to i.v. (0.4 mg/inj) cocaine self-administration. RESULTS: Larger place preferences were associated with faster runway start latencies (r s = -0.64), but not with retreat frequency or run times; larger place aversions predicted slower runway start times (r s = 0.62), increased run times (r s = 0.65), and increased retreats (r s = 0.62); response escalation was observed in both the 1- and 6-h self-administration groups and was associated with increased CPPs (r s = 0.58) but not CPAs, as well as with faster run times (r s = -0.60). CONCLUSIONS: Together, these data suggest that animals exhibiting a greater positive than negative response to acute (single daily injections of) cocaine are at the greatest risk for subsequent escalated cocaine self-administration, a presumed indicator of cocaine addiction.