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Multifunctional Compound AD-35 Improves Cognitive Impairment and Attenuates the Production of TNF-a and IL-1ß in an Aß25-35-induced Rat Model of Alzheimer's Disease.

Authors: Li, Lin  Xu, Shaofeng  Liu, Lifei  Feng, Rentian  Gong, Yongxiang  Zhao, Xuyang  Li, Jiang  Cai, Jie  Feng, Nan  Wang, Ling  Wang, Xiaoliang  Peng, Ying 
Citation: Li L, etal., J Alzheimers Dis. 2017;56(4):1403-1417. doi: 10.3233/JAD-160587.
Pubmed: (View Article at PubMed) PMID:28157092
DOI: Full-text: DOI:10.3233/JAD-160587

The dyshomeostasis of transition metal ions, accumulation of amyloid-ß (Aß) senile plaques and neuroinflammatory response found in the brain of patients with Alzheimer's disease (AD) have been suggested to be involved in AD pathogenesis. Novel compounds capable of targeting metal-Aß species and neuroinflammation would be valuable. AD-35 is such a patented small-molecule compound derived from innovative modification of the chemical structure of donepezil. This compound could moderately inhibit acetylcholinesterase and metal-induced Aß aggregation in vitro and showed disassembly of Aß aggregates. The effects of AD-35 on cognitive impairments and neuroinflammatory changes caused by intracerebroventricular injection of Aß25-35 were studied in rats. Compared to sham group, Aß25-35 injection significantly led to learning and memory deficits, astrocyte activation, and pro-inflammatory cytokines releases (TNF-α and IL-1ß). Further studies indicated that the phosphorylation of extracellular signal-regulated kinase was involved in astrocyte activation and pro-inflammatory cytokines production. Oral administration of AD-35 could markedly attenuate Aß25-35 injection-induced astrocyte activation, pro-inflammatory cytokines TNF-α and IL-1ß release, and memory deficits. On the contrary, donepezil only showed inhibition of IL-1ß production, but failed to block astrocyte activation and TNF-α production. These results showed that AD-35 would be a novel multi-mechanism drug for the prevention and/or treatment of AD.

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CRRD Object Information
CRRD ID: 13792829
Created: 2018-10-02
Species: All species
Last Modified: 2018-10-02
Status: ACTIVE



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RGD is funded by grant HL64541 from the National Heart, Lung, and Blood Institute on behalf of the NIH.