Replies to post #182613 on Anavex Life Sciences Corp (AVXL)

[Investor2014]

“Evidence is mounting that alterations to normal sleep patterns affect disease progression, promoting the appearance of ß-amyloid (Aß) and tau aggregates that are progressively deposited in the brains of patients with Alzheimer’s disease (AD).”

Based on this biochecked information why would A2-73 not help AD progression if shown to improve sleep in controlled trials?

[XenaLives]

Restoration of normal sleep would set healing forces in motion and it's likely that 2-73 can do exactly what is referred to here:

The evidence is stacking up that disrupted sleep is causally linked with the progression of AD, in part due to increased neuronal activity during wakefulness. Does this imply that dampening down synaptic activity could be beneficial in AD by preventing tau release and spread? Probably not, because strong epidemiologic evidence indicates that promoting neural activity through higher levels of education and exercise reduces the risk of developing AD ( Display footnote number: 11 ). Engaging in activities that provide external stimuli is thought to boost cognitive reserve by building robust networks that are more resilient to diverse insults. However, it is possible that brain networks that are active by default in the absence of external input, and that are known to be dysregulated in AD, could be targeted to slow pathological protein accumulation ( Display footnote number: 12 ).

The benefits of sleep have previously been linked with AD in the context of toxic aggregate clearance, including via the glymphatic system. This pathway, which is most active during sleep, allows exchange of proteins between ISF and CSF and their clearance into perivascular spaces and the lymphatic system ( Display footnote number: 9 ). Damage to molecular and cellular components of the glymphatic system during aging, in the course of neurodegenerative disease, and following physical brain trauma is closely linked with the increased presence of tau and Aß in extracellular fluids, the spread of aggregated proteins (including tau) in the brain, and worsened cognition ( Display footnote number: 13, 14 ).

The contribution of astrocytes, an intrinsic component of the glymphatic system, during AD sleep disruption is also of interest. The astrocyte-neuron lactate shuttle responds to increased energy demands of excitatory neurons during wakefulness, increasing lactate release for conversion to glutamate in neurons ( Display footnote number: 5 ). Sleep disruption in AD will affect astrocyte-directed effects on synaptic activity–driven tau release as well as on tau clearance mechanisms.

Sleep deprivation therefore results in abnormal synaptic activity that increases tau release into extracellular spaces, at times when its clearance is impaired by reduced CSF and ISF flow. If this results in the retention of tau species that are able to seed aggregation, tau pathology will spread across the brain, leading to progressive synapse and neuron dysfunction (see the figure). For those at risk of developing AD, treatments to promote sleep, including those already under investigation for Parkinson’s disease ( Display footnote number: 15 ), may have great benefit. The best advice for everyone is to do all we can to maintain a healthy life balance, sleep well, and engage with activities to keep the body and mind healthy.