The switch from short-term to long-term facilitation of the synapses between sensory and motor neurons mediating gill and tail withdrawal reflexes in Aplysia requires CREB-mediated transcription and new protein synthesis. We isolated several downstream genes, one of which encodes a neuron-specific ubiquitin C-terminal hydrolase. This rapidly induced gene encodes an enzyme that associates with the proteasome and increases its proteolytic activity. This regulated proteolysis is essential for long-term facilitation. Inhibiting the expression or function of the hydrolase blocks induction of long-term but not short-term facilitation. We suggest that the enhanced proteasome activity increases degradation of substrates that normally inhibit long-term facilitation. Thus, through induction of the hydrolase and the resulting up-regulation of the ubiquitin pathway, learning recruits a regulated form of proteolysis that removes inhibitory constraints on long-term memory storage.

Widespread cerebral deposition of a 40 -43-amino acid peptide called the amyloid ␤-protein (A␤) in the form of amyloid fibrils is one of the most prominent neuropathologic features of Alzheimer's disease. Numerous studies suggest that A␤ is toxic to neurons by free radical-mediated mechanisms. We have previously reported that melatonin prevents oxidative stress and death of neurons exposed to A␤. In the process of screening indole compounds for neuroprotection against A␤, potent neuroprotective properties were uncovered for an endogenous related species, indole-3-propionic acid (IPA). This compound has previously been identified in the plasma and cerebrospinal fluid of humans, but its functions are not known. IPA completely protected primary neurons and neuroblastoma cells against oxidative damage and death caused by exposure to A␤, by inhibition of superoxide dismutase, or by treatment with hydrogen peroxide. In kinetic competition experiments using free radical-trapping agents, the capacity of IPA to scavenge hydroxyl radicals exceeded that of melatonin, an indoleamine considered to be the most potent naturally occurring scavenger of free radicals. In contrast with other antioxidants, IPA was not converted to reactive intermediates with pro-oxidant activity. These findings may have therapeutic applications in a broad range of clinical situations.Brains of patients afflicted with Alzheimer's disease show abnormal expression of numerous oxidative stress indicators (1-5) as well as extensive evidence of oxidative damage to proteins (6) and nucleic acids (7,8). A prominent feature of the Alzheimer's disease brain is the widespread cerebral deposition of a 40 -43-amino acid peptide called the amyloid ␤-protein (A␤) 1 in the form of amyloid fibrils within senile plaques and in cerebral and meningeal blood vessels (9, 10). A large body of data suggests that A␤ causes neuronal degeneration and death by mechanisms that involve reactive oxygen species reviewed in Ref. 15).Since the severity of the dementia in Alzheimer's disease has been correlated best with the extent of synaptic loss and the degree of neuronal death (16, 17), enhancing neuronal survival has been a primary objective of many therapeutic strategies. We have recently reported that melatonin prevents oxidative stress and death of neurons exposed to the amyloid peptide (18,19). In the process of screening indole compounds as neuroprotective agents, new properties were uncovered for an endogenous species, indole-3-propionic acid (IPA). IPA has previously been identified in the plasma and cerebrospinal fluid of humans, but its functions are not known (20,21). IPA has, like melatonin, a heterocyclic aromatic ring structure with high resonance stability, which led us to suspect similar neuroprotective and antioxidant properties. Here, we report that IPA prevented oxidative stress and death of primary neurons and neuroblastoma cells exposed to A␤. In addition, IPA also showed a strong level of neuroprotection in two other paradigms of oxidative stress. We found...

The formation of a persistently active cAMP-dependent protein kinase (PKA) is critical for establishing long-term synaptic facilitation (LTF) in Aplysia. The injection of bovine catalytic (C) subunits into sensory neurons is sufficient to produce protein synthesis-dependent LTF. Early in the LTF induced by serotonin (5-HT), an autonomous PKA is generated through the ubiquitin-proteasome-mediated proteolysis of regulatory (R) subunits. The degradation of R occurs during an early time window and appears to be a key function of proteasomes in LTF. Lactacystin, a specific proteasome inhibitor, blocks the facilitation induced by 5-HT, and this block is rescued by injecting C subunits. R is degraded through an allosteric mechanism requiring an elevation of cAMP coincident with the induction of a ubiquitin carboxy-terminal hydrolase.

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The accumulation of amyloid-beta and concomitant oxidative stress are major pathogenic events in Alzheimer's disease. Indole-3-propionic acid (IPA, OXIGON) is a potent anti-oxidant devoid of pro-oxidant activity. IPA has been demonstrated to be an inhibitor of beta-amyloid fibril formation and to be a potent neuroprotectant against a variety of oxidotoxins. This review will summarize the known properties of IPA and outline the rationale behind its selection as a potential disease-modifying therapy for Alzheimer's disease.