The Beneficial Effects of Combining Anti-Aβ Antibody NP106 and Curcumin Analog TML-6 on the Treatment of Alzheimer’s Disease in APP/PS1 Mice

Abstract

Alzheimer’s disease (AD) is a progressive neurodegenerative disease with a multifactorial etiology. A multitarget treatment that modulates multifaceted biological functions might be more effective than a single-target approach. Here, the therapeutic efficacy of combination treatment using anti-Aβ antibody NP106 and curcumin analog TML-6 versus monotherapy was investigated in an APP/PS1 mouse model of AD. Our data demonstrate that both combination treatment and monotherapy attenuated brain Aβ and improved the nesting behavioral deficit to varying degrees. Importantly, the combination treatment group had the lowest Aβ levels, and insoluble forms of Aβ were reduced most effectively. The nesting performance of APP/PS1 mice receiving combination treatment was better than that of other APP/PS1 groups. Further findings indicate that enhanced microglial Aβ phagocytosis and lower levels of proinflammatory cytokines were concurrent with the aforementioned effects of NP106 in combination with TML-6. Intriguingly, combination treatment also normalized the gut microbiota of APP/PS1 mice to levels resembling the wild-type control. Taken together, combination treatment outperformed NP106 or TML-6 monotherapy in ameliorating Aβ pathology and the nesting behavioral deficit in APP/PS1 mice. The superior effect might result from a more potent modulation of microglial function, cerebral inflammation, and the gut microbiota. This innovative treatment paradigm confers a new avenue to develop more efficacious AD treatments.

Different Contacted Cell Types Contribute to Acquiring Different Properties in Brain Microglial Cells upon Intercellular Interaction

“…Microglial cells (MGs) are resident immune cells that exert multiple functions in a healthy and pathological brain. MGs are also involved in the pathogenesis of various diseases in the central nervous system, including ischemic stroke, traumatic brain injuries, Alzheimer’s disease, and brain tumors [ 1 , 2 , 3 , 4 , 5 ]. Therefore, insights into microglial regulation are essential in understanding the progress of such diseases.…”

Therapeutic Potential of Microbiota Modulation in Alzheimer’s Disease: A Review of Preclinical Studies

“…The hypothesis from the study of Sun et al [ 20 ] is based on previous evidence that butyrate modulates abnormal GM, suggesting that after being produced in the colon, it can bypass portal circulation and reach the brain. Butyrate enhances the anti-inflammatory activity of peroxisome proliferator-activated receptor γ and exerts neuroprotective effects [ 26 ]. In addition, authors found decreased butyrate levels in APP/PS1 mice compared to wild-type (WT) but increased after treatment.…”

“…Sun et al [ 20 ] suggest that greater microbe richness does not imply a healthy GM but instead could be attributed to varied harmful bacteria. However, treatment helps in having bacterial communities more akin to the WT mice [ 26 ]. After treatment, GM composition showed a significant increase of Deferribacteres, Alloprevotella and S24-7 and decrease of Helicobacteraceae [ 20 ].…”

“…The reduction observed may occur via the increase of ADAM10 protein of AβPP, which cause the inhibition of Aβ production [ 24 ]. However, there are differences across studies on whether significant changes apply to the cortex and/or hippocampus, on the level of decrease in soluble forms of Aβ or tau phosphorylation, when measured using immunohistochemical assays with confocal imaging [ 24 , 26 ]. The reasons for these differences are unclear, according to Abdelhamid et al [ 24 ], probiotics may activate specific brain regions through the vagus afferent nerve.…”

“…The reasons for these differences are unclear, according to Abdelhamid et al [ 24 ], probiotics may activate specific brain regions through the vagus afferent nerve. However, depending on the dose and the pharmacological approach, the treatment can cause more damage than improvement [ 25 , 26 ]. Significant increase in Aβ plaques and gastrointestinal burden have been observed when testing high doses of a classic Tibetan medicine called Byur dMar Nyer lNga Ril Bu ( BdNlRB ).…”