Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0751295 (memory loss)
 3,619 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Individuals with early-stage Alzheimer's disease (AD) suffer from profound failure to form new memories. A novel molecular mechanism with implications for therapeutics and diagnostics is now emerging in which the specificity of AD for memory derives from disruption of plasticity at synapses targeted by neurologically active A beta oligomers (1). We have named these oligomers "ADDLs" (for pathogenic A beta-Derived Diffusible Ligands). ADDLs constitute metastable alternatives to the disease-defining A beta fibrils deposited in amyloid plaques. In AD brain, ADDLs accumulate primarily as A beta 12mers (2) (approximately 54 kDa) and can be found in dot-like clusters distinct from senile plaques (3). Oligomers of equal mass have been reported to occur in tgmouse AD models where they emerge concomitantly with memory failure (4), consistent with ADDL inhibition of LTP (1). In cell biology studies, ADDLs act as pathogenic gain-of-function ligands that target particular synapses, binding to synaptic spines at or near NMDA receptors (5,6). Binding produces ectopic expression of the memory-linked immediate early gene Arc. Subsequent ADDL-induced abnormalities in spine morphology and synaptic receptor composition (7) are predicted consequences of Arc overexpression, a pathology associated with memory dysfunction in tg-Arc mice. Significantly, the attack on synapses provides a plausible mechanism unifying memory dysfunction with major features of AD neuropathology; recent findings show that ADDL binding instigates synapse loss, oxidative damage, and AD-type tau hyperphosphorylation. Acting as novel neurotoxins that putatively account for memory loss and neuropathology, ADDLs present significant targets for disease-modifying therapeutics in AD.
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PMID:Why Alzheimer's is a disease of memory: the attack on synapses by A beta oligomers (ADDLs). 1816 46

Accumulation of amyloid beta (Abeta) oligomers in the brain is toxic to synapses and may play an important role in memory loss in Alzheimer disease. However, how these toxins are built up in the brain is not understood. In this study we investigate whether impairments of insulin and insulin-like growth factor-1 (IGF-1) receptors play a role in aggregation of Abeta. Using primary neuronal culture and immortal cell line models, we show that expression of normal insulin or IGF-1 receptors confers cells with abilities to reduce exogenously applied Abeta oligomers (also known as ADDLs) to monomers. In contrast, transfection of malfunctioning human insulin receptor mutants, identified originally from patient with insulin resistance syndrome, or inhibition of insulin and IGF-1 receptors via pharmacological reagents increases ADDL levels by exacerbating their aggregation. In healthy cells, activation of insulin and IGF-1 receptor reduces the extracellular ADDLs applied to cells via seemingly the insulin-degrading enzyme activity. Although insulin triggers ADDL internalization, IGF-1 appears to keep ADDLs on the cell surface. Nevertheless, both insulin and IGF-1 reduce ADDL binding, protect synapses from ADDL synaptotoxic effects, and prevent the ADDL-induced surface insulin receptor loss. Our results suggest that dysfunctions of brain insulin and IGF-1 receptors contribute to Abeta aggregation and subsequent synaptic loss.
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PMID:Insulin receptor dysfunction impairs cellular clearance of neurotoxic oligomeric a{beta}. 1940 47

Early diagnosis and treatment of Alzheimer's Disease (AD) ultimately will require identification of its pathogenic mechanism. Such a mechanism must explain the hallmark of early AD--a profound inability to form new memories. For many years, the most promising hypothesis maintained that memory failure derived from neuron death induced by insoluble deposits of amyloid fibrils. Newer findings, however, suggest that memory loss, especially in early AD, may be a failure in synaptic plasticity caused by small soluble A beta oligomers ("ADDLs"). ADDLs are neurologically potent toxins that rapidly inhibit long-term potentiation and reversal of long-term depression, classic paradigms for learning and memory. In human samples, ADDLs show striking increases in AD brain and CSF. The ADDL hypothesis is considerably reinforced by nerve cell biology studies showing that ADDLs specifically attack synapses, essentially acting as gain-of-function pathogenic ligands. Selective damage by ADDLs to memory-linked synaptic mechanisms provides an appealing explanation for early AD memory loss and suggests that ADDLs provide a valid target for therapeutics and diagnostics.
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PMID:Synaptic targeting by A beta oligomers (ADDLS) as a basis for memory loss in early Alzheimer's disease. 1959 55