A new organism prevents amyloidogenesis in Alzheimer's disease

Alzheimer's disease (AD) is an irreversible neurodegenerative disease that affects millions of people worldwide. The pathogenesis of AD is complex. It primarily involves two major molecular players - amyloid-beta (Aβ) and tau - which actually have an inherent tendency to produce molecular assemblies that are toxic to neurons. Incomplete understanding of the molecular mechanisms that induce disease onset and maintain disease progression, as well as the lack of efficient models to comprehensively recapitulate the pathogenesis of human disease, have hindered the development of successful treatments for AD. Overall experience with clinical trials of many potential drugs—including recent findings with Aβ monoclonal antibodies—appears to suggest that Aβ targeting is ineffective without concomitant potent challenges to Aβ’s neurotoxic properties. We took advantage of the anti-amyloidogenic properties of the native variant of Aβ (AβA2V) and based on the intranasal delivery of a hexameric peptide (Aβ1-6 A2V) that retains the anti-amyloidogenic ability of the full-length Aβ A2V variant A novel bioinspired strategy for AD was devised. In AD mouse models, this approach was shown to be effective in preventing wild-type Aβ aggregation and avoiding synaptic damage associated with amyloidogenesis. Our preclinical findings are inspired by models of protection already existing in nature that appear to protect human heterozygous Aβ A2V carriers from AD, opening up an unprecedented and promising approach to preventing human disease .


HIV-1 significantly reduces human (h)CD4+ T cells and hCD4/hCD8 ratio; reduces expression of BBB TJ proteins claudin-5, ZO-1, ZO-2; and increases HLA-DR+ cells in brain tissue. Notably, HIV-infected animals showed increases in plasma and brain Aβ-42 and phosphorylated Tau (threonine 181, threonine 231, serine 396, serine 199), which are consistent with GSAP, an enzyme that catalyzes the formation of Aβ ) transcriptional upregulation was associated with loss of MAP 2 and NeuN. and neurofilament-L. Maraviroc treatment significantly reduces blood and brain viral load, prevents HIV-induced loss of neuronal markers and TJ protein; reduces HLA-DR+ cell infiltration in brain tissue, significantly reduces HIV-induced Aβ-42, GSAP and phosphorylation increase in Tau. Maraviroc also reduces Aβ retention and increases Aβ release in human macrophages; reduces receptors for advanced glycation end products (RAGE) and increases low-density lipoprotein receptor-related protein 1 (LRP1) in human brain endothelial cells )expression. Maraviroc induces transendothelial transport of Aβ that is blocked by LRP1 antagonists, but not by RAGE antagonists.

in conclusion

Maraviroc significantly reduces HIV-induced amyloid production, GSAP, phosphorylated Tau, neurodegeneration, BBB changes and leukocyte infiltration into the CNS. Maraviroc increases cellular Aβ efflux and transendothelial Aβ transport through the LRP1 pathway. Thus, therapeutic targeting of CCR5 can reduce viremia, protect the BBB and neurons, increase brain Aβ efflux, and reduce AD-like neuropathology.