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Preclinical studies are essential for translation to disease treatments and effective use in clinical practice. An undue emphasis on single approaches to Alzheimer's disease (AD) appears to have retarded the pace of translation in the field, and there is much frustration in the public about the lack of an effective treatment. We critically reviewed past literature (1990-2014), analyzed numerous data, and discussed key issues at a consensus conference on Brain Ageing and Dementia to identify and overcome roadblocks in studies intended for translation. We highlight various factors that influence the translation of preclinical research and highlight specific preclinical strategies that have failed to demonstrate efficacy in clinical trials. The field has been hindered by the domination of the amyloid hypothesis in AD pathogenesis while the causative pathways in disease pathology are widely considered to be multifactorial. Understanding the causative events and mechanisms in the pathogenesis are equally important for translation. Greater efforts are necessary to fill in the gaps and overcome a variety of confounds in the generation, study design, testing, and evaluation of animal models and the application to future novel anti-dementia drug trials. A greater variety of potential disease mechanisms must be entertained to enhance progress.

SUMMARY1. The isolated frog spinal cord was used to study the effects of picrotoxin, bicuculline, and strychnine on the responses of primary afferents to amino acids. Recording was by sucrose gap technique.2. A series of neutral amino acids was found to depolarize primary afferents. Optimal activity was obtained by an amino acid whose carboxyl and amino groups were separated by a three-carbon chain length (i.e. GABA). Amino acids with shorter (i.e. f-alanine, glycine) or longer (i.e. a-aminovaleric acid, e-aminocaproic acid) distances between the charged groups were less potent. Imidazoleacetic acid was the most potent depolarizing agent tested.3. Picrotoxin and bicuculline antagonized the primary afferent depolarizations of a number of amino acids tested with equal specificity.Depolarizing responses to standard (10-3 M) concentrations of fl-alanine and taurine were completely blocked by these convulsants, while depolarizations to 103 M y-aminobutyric acid (GABA) were only partially antagonized. Glycine responses were unaffected by these agents.4. Strychnine completely blocked ,8-alanine and taurine depolarizations and incompletely antagonized several other neutral amino acids. GABA, glutamate, and glycine depolarizations were not affected.5. These results suggest that there are at least three distinct populations of neutral amino acid receptors on primary afferent terminals: a GABAlike receptor, a taurine/f,-alanine receptor, and a glycine-like receptor. The

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SUMMARY1. In the isolated frog spinal cord picrotoxin, bicuculline, and strychnine were evaluated for their effects on synaptically induced root potentials recorded by the sucrose gap technique.2. Picrotoxin ( > 104 M) completely blocked the dorsal root potential (DRP) elicited by stimulating the ventral root of the same segment (VR-DRP). Although picrotoxin antagonized the DRP elicited by stimulation of either an adjacent dorsal root (DR-DRP) or the lateral column (LC-DRP), a slower component to these potentials appeared and increased in size as the concentration of picrotoxin was increased. Thus picrotoxin brings out a later, picrotoxin resistant component to the DR-DRP and LC-DRP.3. Strychnine (10-10-5 M) reduced and abolished the VR-DRP without prolongation and progressively increased and prolonged the DR-DRP (and LC-DRP) and the DR-VRP. Strychnine in higher concentrations (> 104 M) also reduced the amplitude and prolonged the duration of the compound action potential of afferent fibres.4. These results combined with those presented in the preceding paper (Barker, Nicoll & Padjen, 1975) suggest that (1) a GABA-like transmitter mediates the final step in the DR-DRP and LC-DRP pathways and that (2) either taurine or ,/-alanine may mediate the last step in the VR-DRP pathway.

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