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Lithium has been marketed in the United States of America since the 1970s as a treatment for bipolar disorder. More recently, studies have shown that lithium can improve cognitive decline associated with Alzheimer's disease (AD). However, the current United States Food and Drug Administration-approved lithium pharmaceutics (carbonate and citrate chemical forms) have a narrow therapeutic window and unstable pharmacokinetics that, without careful monitoring, can cause serious adverse effects. Here, we investigated the safety profile, pharmacokinetics, and therapeutic efficacy of LISPRO (ionic co-crystal of lithium salicylate and l-proline), lithium salicylate, and lithium carbonate (Li 2 CO 3 ). We found that LISPRO (8-week oral treatment) reduces β-amyloid plaques and phosphorylation of tau by reducing neuroinflammation and inactivating glycogen synthase kinase 3β in transgenic Tg2576 mice. Specifically, cytokine profiles from the brain, plasma, and splenocytes suggested that 8-week oral treatment with LISPRO downregulates pro-inflammatory cytokines, upregulates anti-inflammatory cytokines, and suppresses renal cyclooxygenase 2 expression in transgenic Tg2576 mice. Pharmacokinetic studies indicated that LISPRO provides significantly higher brain lithium levels and more steady plasma lithium levels in both B6129SF2/J (2-week oral treatment) and transgenic Tg2576 (8-week oral treatment) mice compared with Li 2 CO 3 . Oral administration of LISPRO for 28 weeks significantly reduced β-amyloid plaques and tau-phosphorylation. In addition, LISPRO significantly elevated pre-synaptic (synaptophysin) and post-synaptic protein (post synaptic density protein 95) expression in brains from transgenic 3XTg-AD mice. Taken together, our data suggest that LISPRO may be a superior form of lithium with improved safety and efficacy as a potential new disease modifying drug for AD.

Alzheimer's disease (AD), a progressive neurodegenerative disorder that is the most common cause of dementia in the elderly, is characterized by the accumulation of amyloid-β (Aβ) plaques and neurofibrillary tangles, as well as a progressive loss of synapses and neurons in the brain. The major pertinacious component of amyloid plaques is Aβ, a variably sized peptide derived from the integral membrane protein amyloid precursor protein (APP). The Aβ region of APP locates partly within its ecto- and trans-membrane domains. APP is cleaved by three proteases, designated as α-, β-, and γ-secretases. Processing by β- and γ-secretase cleaves the N- and C-terminal ends of the Aβ region, respectively, releasing Aβ, whereas α-secretase cleaves within the Aβ sequence, releasing soluble APPα (sAPPα). The γ-secretase cleaves at several adjacent sites to yield Aβ species containing 39-43 amino acid residues. Both α- and β-cleavage sites of human wild-type APP are located in APP672-699 region (ectodomain of β-C-terminal fragment, ED-β-CTF or ED-C99). Therefore, the amino acid residues within or near this region are definitely pivotal for human wild-type APP function and processing. Here, we report that one ED-C99-specific monoclonal antibody (mAbED-C99) blocks human wild-type APP endocytosis and shifts its processing from α- to β-cleavage, as evidenced by elevated accumulation of cell surface full-length APP and β-CTF together with reduced sAPPα and α-CTF levels. Moreover, mAbED-C99 enhances the interactions of APP with cholesterol. Consistently, intracerebroventricular injection of mAbED-C99 to human wild-type APP transgenic mice markedly increases membrane-associated β-CTF. All these findings suggest that APP672-699 region is critical for human wild-type APP processing and may provide new clues for the pathogenesis of sporadic AD.