Peripheral nervous system (
PNS
) neurons support axon regeneration into adulthood, whereas central nervous system (
CNS
) neurons lose regenerative ability after development. To better understand this decline whilst aiming to improve regeneration, we focused on phosphoinositide 3‐kinase (
PI
3K) and its product phosphatidylinositol (3,4,5)‐trisphosphate (
PIP
3
). We demonstrate that adult
PNS
neurons utilise two catalytic subunits of
PI
3K for axon regeneration: p110α and p110δ. However, in the
CNS
, axonal
PIP
3
decreases with development at the time when axon transport declines and regenerative competence is lost. Overexpressing p110α in
CNS
neurons had no effect; however, expression of p110δ restored axonal
PIP
3
and increased regenerative axon transport. p110δ expression enhanced
CNS
regeneration in both rat and human neurons and in transgenic mice, functioning in the same way as the hyperactivating H1047R mutation of p110α. Furthermore, viral delivery of p110δ promoted robust regeneration after optic nerve injury. These findings establish a deficit of axonal
PIP
3
as a key reason for intrinsic regeneration failure and demonstrate that native p110δ facilitates axon regeneration by functioning in a hyperactive fashion.
Alzheimer's disease (AD) is the most common cause of dementia, affecting 35 million people worldwide. One pathological feature of progressing AD is the loss of synapses. This is the strongest correlate of cognitive decline. Astrocytes, as an essential part of the tripartite synapse, play a role in synapse formation, maintenance, and elimination. During AD, astrocytes get a reactive phenotype with an altered gene expression profile and changed function compared to healthy astrocytes. This process likely affects their interaction with synapses. This systematic review aims to provide an overview of the scientific literature including information on how astrocytes affect synapse formation and elimination in the brain of AD patients and in animal models of the disease. We review molecular and cellular changes in AD astrocytes and conclude that these predominantly result in lower synapse numbers, indicative of decreased synapse support or even synaptotoxicity, or increased elimination, resulting in synapse loss, and consequential cognitive decline, as associated with AD. Preventing AD induced changes in astrocytes might therefore be a potential therapeutic target for dementia.Systematic Review Registration:https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=148278, identifier [CRD148278].
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