Alzheimer’s disease (AD) is the most common neurodegenerative disorder characterized by progressive loss of memoryand cognitive function. The cerebral metabolic rate of glucose oxidation has been shown to be reduced in AD. The presentstudy evaluated efficacy of dietary Amalaki Rasayana (AR), an Ayurvedic formulation used in Indian traditional system, inAβPP-PS1 mouse model of AD in ameliorating memory and neurometabolism, and compared with donepezil, a standardFDA approved drug for AD. The memory of mice was measured using Morris Water Maze analysis. The cerebralmetabolism was followed by 13C labelling of brain amino acids in tissue extracts ex vivo using ${}^{1}$H-[${}^{13}$C]-NMR spectroscopytogether with a short time infusion of [1,6-${}^{13}$C2]glucose to mice. The intervention with Amalaki Rasayana showedimproved learning and memory in AbPP-PS1 mice. The ${}^{13}$C labelings of GluC4, GABAC2 and GlnC4 were reduced inAbPP-PS1 mice when compared with wild-type controls. Intervention of AR increased the ${}^{13}$C labelling of amino acidssuggesting a significant enhancement in glutamatergic and GABAergic metabolic activity in AβPP-PS1 mice similar to thatobserved with donepezil treatment. These data suggest that AR has potential to improve memory and cognitive function inAD.

Systemic delivery of nucleic acids to the central nervous system (CNS) is a major challenge for the development of RNAinterference-based therapeutics due to lack of stability, target specificity, non-permeability to the blood–brain barrier (BBB),and lack of suitable carriers. Using a designed bi-functional fusion protein TARBP-BTP in a complex with siRNA, weearlier demonstrated knockdown of target genes in the brain of both AbPP-PS1 (Alzheimer’s disease, AD) and wild-typeC57BL/6 mice. In this report, we further substantiate the approach through an extended use in AbPP-PS1 mice, which upontreatment with seven doses of b-secretase AbPP cleaving Enzyme 1 (BACE1) TARBP-BTP:siRNA, led to target-specificeffect in the mouse brain. Concomitant gene silencing of BACE1, and consequent reduction in plaque load in the cerebralcortex and hippocampus ([60%) in mice treated with TARBP-BTP:siRNA complex, led to improvement in spatial learningand memory. The study validates the efficiency of TARBP-BTP fusion protein as an efficient mediator of RNAi, givingconsiderable scope for future intervention in neurodegenerative disorders through the use of short nucleic acids as genespecific inhibitors.