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)

Alzheimer's disease (AD) is the most prevalent neurodegenerative disease worldwide. It is a progressive, incurable disease whose predominant clinical manifestation is memory loss, and which always ends in death. The classic neuropathological diagnostic markers for AD are amyloid plaques and neurofibrillary tangles, but our understanding of the role that these features of AD play in the etiology and progression of the disease remains incomplete. Research over the last decade has revealed that cell cycle abnormalities also represent a major neuropathological feature of AD. These abnormalities appear very early in the disease process, prior to the appearance of plaques and tangles. Growing evidence suggests that neuronal cell cycle regulatory failure, leading to apoptosis, may be a significant component of the pathogenesis of AD. A number of signaling pathways with the potential to activate aberrant cell cycle re-entry in AD have been described. The relationships among these signaling cascades, which involve the amyloid precursor protein (APP), cyclin-dependent kinases (cdks), and the cell cycle protein Pin1, have not yet been fully elucidated, but details of the individual pathways are beginning to emerge. This review summarizes the current state of knowledge with respect to specific neuronal signaling events that are thought to underlie cell cycle regulatory failure in AD brain. The elements of these pathways that represent potential new therapeutic targets for AD are described. Drugs and peptides that can inhibit molecular steps leading to AD neurodegeneration by intervening in the activation of cell cycle re-entry in neurons represent an entirely new approach to the development of treatments for AD.
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PMID:The cell cycle as a therapeutic target for Alzheimer's disease. 1627 48

After protein phosphorylation on certain serine or threonine residues preceding a proline (pSer/Thr-Pro), the function of certain phosphorylated protein is further regulated by cis-trans conformational change. Due to the lack of any tool to detect such two conformations in cells, however, it is not even known whether any cis or trans conformation exists in vivo, not to mention their conformation-specific functions or regulation. We developed a novel peptide chemistry technology to generate the first pair of antibodies that can distinguish cis from trans pThr231-Pro tau. Cis, but not trans, pThr231-tau appears early in mild cognitive impairment (MCI) neurons and further accumulates in only degenerating neurons as Alzheimer disease (AD) progresses, localizing to dystrophic neurites, which are known to correlate well with memory loss. Unlike trans p-tau, the cis cannot promote microtubule assembly, and is more resistant to dephosphorylation and degradation and more prone to aggregation. Pin1 accelerates cis to trans isomerization to prevent tau pathology in AD. Thus, during MCI and AD development, cis pThr231-Pro tau is the earliest detectable pathogenic tau conformation and antibodies and vaccines against the pathogenic cis p-tau may be used for the early diagnosis and treatment of AD. These findings offer in vivo approach to study conformational regulation of Pro-directed phosphorylation signaling.
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PMID:Cis phosphorylated tau as the earliest detectable pathogenic conformation in Alzheimer disease, offering novel diagnostic and therapeutic strategies. 2315 34

Proline-directed protein phosphorylation (pSer/Thr-Pro), a central signaling mechanism in diverse cellular processes in physiology and disease, has been proposed to be subject to further cis-trans conformational regulation by the unique prolyl isomerase Pin1. Until recently, no tool is available to directly detect the cis-trans conformation of Pin1-catalyzed cis-trans conformational changes in vivo. We have developed novel peptide chemistry that enables to generate the first antibodies that can distinguish cis from trans pThr231-Pro conformation in tau (p-tau). Using these conformation-specific antibodies, we have discovered that cis, but not trans, p-tau appears early in mild cognitive impairment (MCI) neurons and further accumulates in neurofibrillary degenerated neurons as Alzheimer's disease (AD) progresses, localizing to the dystrophic neurites, an early hallmark change that correlates with synaptic and cognitive deficits. Unlike trans p-tau, the cis not only cannot promote microtubule assembly, but also is more resistant to dephosphorylation and degradation, and prone to aggregation. Pin1 accelerates cis to trans conversion to prevent the accumulation of the pathogenic cis p-tau conformation in AD, providing the first structural evidence for how Pin1 protects against AD. These findings develop the first tool to directly detect cis-trans prolyl isomerization, especially after phosphorylation and uncover cis p-tau as the very early pathogenic conformation leading to tau pathology and memory loss in AD. These results also suggest novel conformation-specific diagnoses and therapies for AD and likely others.
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PMID:Distinct functions of cis and trans phosphorylated tau in Alzheimer's disease and their therapeutic implications. 2315 76