Preformulation Studies of a Stable PTEN-PDZ Lipopeptide Able to Cross an In Vitro Blood-Brain-Barrier Model as a Potential Therapy for Alzheimer’s Disease

Abstract

Purpose Amyloid β (Aβ) drives the accumulation of excess Phosphatase and Tensin Homolog Deleted on Chromosome 10 (PTEN) at synapses, inducing synaptic depression and perturbing memory. This recruitment of PTEN to synapses in response to Aβ drives its interaction with PSD95/Disc large/Zonula occludens-1 (PDZ) proteins and, indeed, we previously showed that an oligo lipopeptide (PTEN-PDZ) capable of blocking such PTEN:PDZ interactions rescues the synaptic and cognitive deficits in a mouse model of Alzheimer’s disease. Hence, the PTEN:PDZ interaction appears to be crucial for Aβ-induced synaptic and cognitive impairment. Here we have evaluated the feasibility of using PTEN-PDZ lipopeptides based on the human/mouse PTEN C-terminal sequence, testing their stability in biological fluids, their cytotoxicity, their ability to self-assemble and their in vitro blood-brain barrier (BBB) permeability. Myristoyl or Lauryl tails were added to the peptides to enhance their cell permeability. Methods Lipopeptides self assembly was assessed using electron microscopy and the thioflavin T assay. Stability studies in mouse plasma (50%), intestinal washing, brain and liver homogenates as well as permeability studies across an all human 2D blood-brain barrier model prepared with human cerebral endothelial cells (hCMEC/D3) and human astrocytes (SC-1800) were undertaken. Results The mouse lauryl peptide displayed enhanced overall stability in plasma, ensuring a longer half-life in circulation that meant there were larger amounts available for transport across the BBB (Papp0-4h: 6.28 ± 1.85 × 10−6 cm s−1). Conclusion This increased availability, coupled to adequate BBB permeability, makes this peptide a good candidate for therapeutic parenteral (intravenous, intramuscular) administration and nose-to-brain delivery. Graphical Abstract

Aberrant Synaptic PTEN in Symptomatic Alzheimer’s Patients May Link Synaptic Depression to Network Failure

“…Indeed, a peptide has been designed based on PTEN’s C-terminal sequence that can block this PTEN/PSD-95 interaction and it has been successfully tested in AD model mice ( Knafo et al, 2016 ). Subsequent studies showed that derivatives of the original peptide are stable in plasma and they are capable of crossing the blood-brain barrier in vitro ( Lalatsa et al, 2020 ). Nevertheless, before continuing to develop therapies based on overcoming this pathological mechanism, it is imperative to detect parallel pathological alterations in diseased human brains.…”

Biomarker profiling to determine clinical impact of microRNAs in cognitive disorders

“…In an AD mouse model, plasma PTEN-PDZ complex is relatively stable and crosses the BBB to become PTEN, resulting in synaptic protection and improved cognitive function. These two characteristics (plasma stability and BBB permeability) make the PTEN-PDZ complex a promising candidate for parenteral (intravenous and intramuscular) and naso-cerebral administration 74 .…”

ACTH-secreting pituitary carcinoma with TP53, NF1, ATRX and PTEN mutations Case report and review of the literature

“…PTEN protein is built up of different domains including phosphatase domain [30,31], which is responsible for converting PI (3,4,5) P 3 to PI (4,5) P 2 and thus antagonizing the PI3K pathway 32 . Both PTEN c.210-1 G > A and p.R130* mutations (Fig.…”

“…NF1, TP53, and PTEN mutations lead to activation of several well-known signaling pathways (RAS, RAF, MAPK, ERK, PI3K, Akt) [22][23][24][25][26][27][28][29][30][31][32][33][34][35] (Fig. 6).…”