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Changes in hippocampal function seem critical for cognitive impairment in Alzheimer's disease (AD). Although there is eventual loss of synapses in both AD and animal models of AD, deficits in spatial memory and inhibition of long-term potentiation (LTP) precede morphological alterations in the models, suggesting earlier biochemical changes in the disease. In the studies reported here we demonstrate that amyloid [beta]-peptide (A[beta]) treatment of cultured hippocampal neurons leads to the inactivation of protein kinase A (PKA) and persistence of its regulatory subunit PKAII[alpha]. Consistent with this, CREB phosphorylation in response to glutamate is decreased, and the decrease is reversed by rolipram, a phosphodiesterase inhibitor that raises cAMP and leads to the dissociation of the PKA catalytic and regulatory subunits. It is likely that a similar mechanism underlies A[beta] inhibition of LTP, because rolipram and forskolin, agents that enhance the cAMP-signaling pathway, can reverse this inhibition. This reversal is blocked by H89, an inhibitor of PKA. These observations suggest that A[beta] acts directly on the pathways involved in the formation of late LTP and agents that enhance the cAMP/PKA/CREB-signaling pathway have potential for the treatment of AD.

The effects of ubiquitin C-terminal hydrolase L1 (Uch-L1) inhibition on LTP and memory was investigated to determine the increasing Uch activity by the application of a fusion protein containing Uch-L1 rescues synaptic dysfunction in hippocampal slices treated with oligomeric A[beta]. The data results suggest that Uch-L1 could be an attractive target for the development of new therapeutic approaches to Alzheimer's disease (AD), either alone or in combination with therapies that alter A[beta] levels.