Alzheimer's and Dementia: Target app, Posiphen can treat Down syndrome.

Recent clinical trials of amyloid beta (A beta) and tau in Alzheimer's disease (AD) have yet to show efficacy.
reviewing the hypothesis of AD pathogenesis and defining possible links between them will enhance our understanding of upstream initiative events and downstream mechanisms, thereby facilitating the discovery of new treatments.
There is evidence that increased doses of the APP gene are necessary for both AD neuropathy and dementia in down syndrome (DS), a significantly pre-employment AD population, suggesting that normalization of levels of amyloid prebiotic proteins (DPs) and their products is a way to further clarify the pathogenesis of AD and to discover new treatments.
previous studies have shown that AD and DS share several common characteristics.
DS is caused by all or part of the trisomy syndrome of chromosome 21, which contains about 233 protein-coding genes, including APP.
recent evidence suggests that the expression of the APP gene and its 99 amino acid C-end fragments (C99, also known as beta-CTF) plays a decisive role in the neural/lysosome system disorder.
the latter is essential for the transmission of neurotrophic signals in normal cellular function and neurons.
Therefore, the researchers hypothesically, the increase in the dose of the APP gene in DS initiates a process in which the levels of the full-length APP (fl-APP) and its products, including beta-CTF and possibly A-beta peptides (A-beta 42 and A-beta-40), increase, drive the onset of AD through endometrial dependence mechanisms, thereby impairing the transport of neurotrophic signals.
to test this hypothesis, the researchers studied the DS model in Ts65Dn mice and examined Posiphen's effect.
Posiphen is an oral small molecule that has been shown in previous studies to reduce fl-APP.
in-body, Posiphen reduces fl-APP and its C-side fragments, reverses Rab5 overactivation and early endometrial enlargement, and restores retrograde transport of neuronutrient signals.
in the body, Posiphen therapy (50mg/kg/d, 26 days, intra-abdominal (i.p.)) Ts65Dn mice had good tolerance and showed no adverse behavioural effects.
results showed that Posiphen therapy led to normalization of fl-APP, C-side fragments and A-beta levels, Rab5 activity returned to normal levels, phosphatization tau (p-tau) decreased, and reversal of TrkB (inositol-inositive kinase B), and Akt (protein kinase B (PKB),) and ERK (extracellular signal-regulating kinase), as well as CREB (cAMP reaction element binding protein) signaling defects.
note that Posiphen therapy also restores levels of acetylcholine transferase protein to 2N levels.
The results support the APP gene dose hypothesis, and more research is needed to explore the mechanisms by which APP gene expression increases the risk of AD in DS, as well as the possible effects of treatments that normalize the level of APP and its products to prevent the onset of AD in DS patients."
important unanswered questions in the study: 1. (1) When should DS patients be intervened; (2) whether app-based strategies will have adverse consequences for possible adaptive changes caused by long-term increases in the dose of the APP gene; (3) whether other genes present on chromosome 21, or other chromosomes that express disorders in DS, contribute to the onset of AD; and (4) whether a model can be established that will combine APP-based therapy with treatment for other AD esoteric forms, including p-tau and inflammation.
the APP gene dose hypothesis is linked to AD's amyloid protein cascading hypothesis, as well as the gene and cell biology observations that support the hypothesis.
addition, the increase in fl-APP proteins and products may drive downstream events, causing tau balance and inflammatory response disorders, thereby facilitating the spread of AD pathogenesis.
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