AZP2006, a new promising treatment for Alzheimer’s and related diseases

Abstract

Progranulin (PGRN) is a protein with multiple functions including the regulation of neuroinflammation, neuronal survival, neurite and synapsis growth. Although the mechanisms of action of PGRN are currently unknown, its potential therapeutic application in treating neurodegenerative diseases is huge. Thus, strategies to increase PGRN levels in patients could provide an effective treatment. In the present study, we investigated the effects of AZP2006, a lysotropic molecule now in phase 2a clinical trial in Progressive Supranuclear Palsy patients, for its ability to increase PGRN level and promote neuroprotection. We showed for the first time the in vitro and in vivo neuroprotective effects of AZP2006 in neurons injured with Aβ1–42 and in two different pathological animal models of Alzheimer’s disease (AD) and aging. Thus, the chronic treatment with AZP2006 was shown to reduce the loss of central synapses and neurons but also to dramatically decrease the massive neuroinflammation associated with the animal pathology. A deeper investigation showed that the beneficial effects of AZP2006 were associated with PGRN production. Also, AZP2006 binds to PSAP (the cofactor of PGRN) and inhibits TLR9 receptors normally responsible for proinflammation when activated. Altogether, these results showed the high potential of AZP2006 as a new putative treatment for AD and related diseases.

A Polyaminobiaryl-Based β-secretase Modulator Alleviates Cognitive Impairments, Amyloid Load, Astrogliosis, and Neuroinflammation in APPSwe/PSEN1ΔE9 Mice Model of Amyloid Pathology

“…Helping to keep or bring glial cells back into this clearance and phagocytosis stage before the activation and pathology worsening phase, as the PEL24-199 molecule seems to do, could thus be an interesting therapeutic strategy. These results are consistent with a recently published study showing that AZP2006, a related compound, possessed neuroprotective properties in two animal models of AD and aging [ 75 ]. Thus, the beneficial effects of AZP2006 were linked to the inflammation regulator progranulin and the inhibition of TLR9 receptors that are normally responsible for proinflammation when activated.…”

Hypoxic Preconditioned Neural Stem Cell-Derived Extracellular Vesicles Contain Distinct Protein Cargo from Their Normal Counterparts

“…P-Tau protein accumulation may be influenced by decreasing Psap levels and their interactions in neurons [ 72 ]. Other studies have suggested that Psap may play a role in Alzheimer’s disease [ 73 , 74 , 75 ]. Psap has also been linked to neurotrophic and cell-damaging effects [ 76 , 77 , 78 ].…”

Pharmacotherapies for the Treatment of Progressive Supranuclear Palsy: A Narrative Review

“…AZP2006, a small molecule and lead compound of the piperazine family, is another potential treatment that is being studied for its efficacy in treating AD and other related disorders, including PSP. In a study published in 2021, AZP2006 increased levels of the protein progranulin (PGRN) [127]. PGRN is a glycoprotein that is secreted or transported to lysosomes in neurons and the immune system [127].…”

“…In a study published in 2021, AZP2006 increased levels of the protein progranulin (PGRN) [127]. PGRN is a glycoprotein that is secreted or transported to lysosomes in neurons and the immune system [127]. It is associated with regulating neuroinflammation, neurite branching and outgrowth, lysosome function, and neuron survival [127].…”

“…PGRN is a glycoprotein that is secreted or transported to lysosomes in neurons and the immune system [127]. It is associated with regulating neuroinflammation, neurite branching and outgrowth, lysosome function, and neuron survival [127]. High levels of PGRN, broken down into granulin, are associated with pathological conditions, while low circulating levels are associated with neurodegenerative diseases such as FTD [127].…”