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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.

We present the case of a 61-year-old retired catholic priest, who was adopted at a very young age, with psychiatric history of anxiety and depression presenting for evaluation of at least 4 year memory loss and word finding difficulties. Over the preceding couple of years his cognitive functions had rapidly declined. As a result, he became dependent on his elderly parents for most of his instrumental activities of daily living including administration of medication, financial management, and driving. He continues to be independent in his personal care. His presentation offered diagnostic challenges due to the interplay of anxiety and cognitive disorders involving both memory and language domains. In addition, he resisted to repeat formal neuropsychological evaluation. At the bedside, his poor effort on testing was often blamed on his severe anxiety confounding the clinical picture. Lack of knowledge of his family history and his childhood development, and unclear premorbid functioning complicated the diagnostic formulation. A differential diagnosis ranging from possible functional cognitive disorder to neurodevelopmental disorder and neurodegenerative disorders will be discussed. [ABSTRACT FROM AUTHOR]

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.

Elevated levels of amyloid-beta peptide (Abeta) are found in Down's syndrome patients and alter synaptic function during the early stages of Alzheimer's disease. Dendritic spines, sites of most excitatory synaptic contacts, are considered to be an important locus for encoding synaptic plasticity. We used time-lapse two-photon imaging of hippocampal pyramidal neurons in organotypic slices to study the effects of Abeta on the development of dendritic spines. We report that exposure of hippocampal neurons to sub-lethal levels of Abeta decreased spine density, increased spine length and subdued spine motility. The effect of Abeta on spine density was reversible. Moreover, Abeta's effect on dendritic spine density was blocked by rolipram, a phosphodiesterase type IV inhibitor, suggesting the involvement of a cAMP dependent pathway. These findings raise the possibility that Abeta-induced spine alterations could underlie the cognitive defects in Alzheimer's disease and Down syndrome.

The neuronal ubiquitin/proteasomal pathway has been implicated in the pathogenesis of Alzheimer's disease (AD). We now show that a component of the pathway, ubiquitin C-terminal hydrolase L1 (Uch-L1), is required for normal synaptic and cognitive function. Transduction of Uch-L1 protein fused to the transduction domain of HIV-transactivator protein (TAT) restores normal enzymatic activity and synaptic function both in hippocampal slices treated with oligomeric Abeta and in the APP/PS1 mouse model of AD. Moreover, intraperitoneal injections with the fusion protein improve the retention of contextual learning in APP/PS1 mice over time. The beneficial effect of the Uch-L1 fusion protein is associated with restoration of normal levels of the PKA-regulatory subunit IIalpha, PKA activity, and CREB phosphorylation.