Compensating for Cognitive Decline in Alzheimer's Disease

In this open access paper researchers report on a way to somewhat compensate for the measurable cognitive dsyfunction resulting from Alzheimer's disease by boosting synaptic activity. This is characteristic of much of what emerges from the medical research community in that it makes no attempt to engage with the causes of the condition, but rather adjusts biological processes so as to better force continued operation despite the underlying disease pathology:

A series of recent studies have found that the levels of the enzyme striatal-enriched protein tyrosine phosphatase (STEP) are raised in several different neuropsychiatric and neurodegenerative disorders, including Alzheimer's disease, fragile X syndrome, and schizophrenia. STEP normally opposes the development of synaptic strengthening, and these abnormally high levels of active STEP disrupt synaptic function by removing phosphate groups from a number of proteins, including several glutamate receptors and kinases. Dephosphorylation results in internalization of the glutamate receptors and inactivation of the kinases - events that disrupt the consolidation of memories.

The increase in STEP activity [likely] contributes to the cognitive deficits in AD. AD mice lacking STEP have restored levels of glutamate receptors on synaptosomal membranes and improved cognitive function, results that suggest STEP as a novel therapeutic target for AD. Here we identify the benzopentathiepin 8-(trifluoromethyl)-1,2,3,4,5-benzopenta‚Äčthiepin-6-aminehydrochloride (known as TC-2153) as a novel inhibitor of STEP, and we demonstrate the activity of TC-2153 both in vitro and in vivo. TC-2153 shows specificity towards STEP compared to several other tyrosine phosphatases and shows no toxicity to cultured neurons. Importantly, the compound reversed cognitive deficits in a mouse model of Alzheimer's disease in a way that did not involve changes in the usual pathological signs (p-tau and beta-amyloid).



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