INTRODUCTION:Pharmacological restoration of septin filament integrity has the potential to provide symptomatic benefit and disease modification in Alzheimer's disease (AD). METHODS:REM127, a septin modulator, was assessed in mild-to-moderate AD (EudraCT: 2022-000080-43) in a phase 2a trial (n = 14). PRIMARY ENDPOINTS:safety and tolerability; exploratory endpoints: pharmacokinetics, cerebrospinal fluid (CSF) biomarkers, electroencephalography (EEG), and functional outcomes. RESULTS:In participants on active therapy, dose-dependent increases in serum aminotransferase were observed, leading to study discontinuation. CSF hyperphosphorylated tau (P-tau181), endpoints reflecting synaptic function and cognitive outcomes, were changed significantly (p < 0.05) to normal compared to placebo. DISCUSSION:REM127 triggers off-target liver adverse effects. Anticipated on-target outcomes suggest septin modulation has symptomatic benefit and modifies processes underlying AD. Results are considered exploratory as statistical power is constrained due to the small sample size caused by early termination. Further investigation of the therapeutic concept using an optimized septin molecular glue with an improved safety profile is warranted. HIGHLIGHTS:Septin 6/7 molecular glue REM127 was assessed in symptomatic participants with Alzheimer's disease (AD). REM127 triggers off-target effects suggesting liver adverse effects. REM127 brain exposure was consistent with saturated target engagement. Biomarker and cognitive outcomes were changed consistent with therapeutic benefit. Septin modulation may restore synaptic function and mitigate pathology in AD.

p75 neurotrophin receptor (p75NTR) signaling pathways substantially overlap with degenerative networks active in Alzheimer disease (AD). Modulation of p75NTR with the first-in-class small molecule LM11A-31 mitigates amyloid-induced and pathological tau-induced synaptic loss in preclinical models. Here we conducted a 26-week randomized, placebo-controlled, double-blinded phase 2a safety and exploratory endpoint trial of LM11A-31 in 242 participants with mild to moderate AD with three arms: placebo, 200 mg LM11A-31 and 400 mg LM11A-31, administered twice daily by oral capsules. This trial met its primary endpoint of safety and tolerability. Within the prespecified secondary and exploratory outcome domains (structural magnetic resonance imaging, fluorodeoxyglucose positron-emission tomography and cerebrospinal fluid biomarkers), significant drug-placebo differences were found, consistent with the hypothesis that LM11A-31 slows progression of pathophysiological features of AD; no significant effect of active treatment was observed on cognitive tests. Together, these results suggest that targeting p75NTR with LM11A-31 warrants further investigation in larger-scale clinical trials of longer duration. EU Clinical Trials registration: 2015-005263-16 ; ClinicalTrials.gov registration: NCT03069014 .

The p75 neurotrophin receptor (p75NTR) modulates pro- and anti-apoptotic pathways as well as neurite and neuritic spine integrity. This receptor is expressed in cells vulnerable to aging and disease, including basal forebrain cholinergic neurons and hippocampal pyramidal neurons. It is also expressed by glial cells under pathological conditions. Pharmacological modulation of the p75NTR with LM11A-31 alters both age- and disease-related neuronal dysfunction. For example, LM11A-31 reverses neuritic pathology in aged mice and reduces amyloid-induced tau phosphorylation in mouse models of Alzheimer’s disease (AD). In this proof-of-concept study, we examined the effects of LM11A-31 treatment on longitudinal neuroimaging and CSF biomarkers in humans with mild to moderate Alzheimer’s disease. Based on our preclinical work, we hypothesized that age and disease may interact to predict response to LM11A-31 treatment in humans. Therefore, we additionally conducted subgroup analyses of drug effect in older and younger individuals. Participants with mild to moderate AD (MMSE score = 18-26; age 55-85 years) were enrolled in a 26-week placebo-controlled phase 2a safety and exploratory endpoint trial of LM11A-31. Exploratory outcome measures included structural MRI, CSF AD core biomarkers, and CSF biomarkers related to pathological processes affected in mouse studies including synaptic integrity and inflammation. For placebo and drug, age subgroups were defined using a median-split: younger (<72 years) and older (> = 72 years). Whole brain structural MRI analyses revealed that 26-week treatment with LM11A-31 reduced longitudinal grey matter degeneration in AD-vulnerable brain regions including the inferior temporal gyrus, insula, frontal operculum and retrosplenial cortex. Furthermore, drug treatment, compared to placebo, prevented longitudinal increases of CSF tau, the presynaptic biomarker SNAP25, and the inflammatory biomarker YKL-40. Median split analyses demonstrated that drug effects for structural MRI and CSF measures were consistently stronger in younger individuals. This investigation highlights that biomarkers may demonstrate age-dependency in response to therapeutic interventions in the context of mild-moderate AD. Our results may inform biomarker selection and design of future studies of LM11A-31 in human AD.

Abstract Over 5 million Americans and 50 million individuals worldwide are living with Alzheimer's disease (AD). The progressive dementia associated with AD currently has no cure. Although clinical trials in patients are ultimately required to find safe and effective drugs, animal models of AD permit the integration of brain pathologies with learning and memory deficits that are the first step in developing these new drugs. The purpose of the Alzheimer's Association Business Consortium Think Tank meeting was to address the unmet need to improve the discovery and successful development of Alzheimer's therapies. We hypothesize that positive responses to new therapies observed in validated models of AD will provide predictive evidence for positive responses to these same therapies in AD patients. To achieve this goal, we convened a meeting of experts to explore the current state of AD animal models, identify knowledge gaps, and recommend actions for development of next‐generation models with better predictability. Among our findings, we all recognize that models reflecting only single aspects of AD pathogenesis do not mimic AD. Models or combinations of new models are needed that incorporate genetics with environmental interactions, timing of disease development, heterogeneous mechanisms and pathways, comorbidities, and other pathologies that lead to AD and related dementias. Selection of the best models requires us to address the following: (1) which animal species, strains, and genetic backgrounds are most appropriate; (2) which models permit efficient use throughout the drug development pipeline; (3) the translatability of behavioral‐cognitive assays from animals to patients; and (4) how to match potential AD therapeutics with particular models. Best practice guidelines to improve reproducibility also need to be developed for consistent use of these models in different research settings. To enhance translational predictability, we discuss a multi‐model evaluation strategy to de‐risk the successful transition of pre‐clinical drug assets to the clinic.

More and more data suggest that the toxic protein assemblies of Aβ and TAU behave prion like. The drug candidate PRI‐002 has been developed to directly disassemble and destroy toxic Aβ oligomer prions. The anti‐prionic compound PRI‐002 (alias “RD2”) is BBB penetrable and has demonstrated target engagement in vitro and in vivo. Treatments in three different transgenic mouse models in three different laboratories yielded improved cognition and deceleration of neurodegeneration. Oral treatment of old‐aged transgenic AD mice with full‐blown pathology reversed cognitive and behavioral deficits to levels of healthy wild‐type littermates. We wanted to demonstrate safety and tolerability of PRI‐002 in healthy volunteers up to doses that are much higher than the expected therapeutic dose.

AbstractBackgroundAn ambitious primary goal of NAPA is to identify disease modifying interventions, a goal complicated by the nearly complete failure of all clinical trials. However, a common yet neglected target is the pathophysiology progression theme of synaptic dysfunction associated with aspects of neuroinflammation that contribute to synaptic dysfunction. The neuroinflammation‐synaptic dysfunction hypothesis posits that certain aspects of this axis are amenable to therapeutic intervention. The druggable stress kinase p38αMAPK is a key target in the neuroinflammation‐synaptic dysfunction pathophysiology progression axis. Increased activity in activated glia results in dysregulated innate immunity as evidenced by increased levels of proinflammatory cytokines. Increased activity in neurons results in altered axonal transport and synaptic dysfunction. Neuronal dysfunction, in turn, results in further stimulation of the evolving stress cycle. Concurrent inhibition of the single target p38αMAPK in distinct cells of the pathophysiology axis could provide a novel form of potential pleiotropic intervention with increased potential for efficacy.MethodA fragment‐based, secondary pharmacology‐filtered experimental approach allowed the custom design and production of a novel p38αMAPKI drug candidate, MW150 (= MW01‐18‐150SRM), with exceptional molecular selectivity and concurrent avoidance of dose limiting barriers identified in prior clinical candidates. IND‐enabling preclinical toxicology integrated with preclinical pharmacokinetics and pharmacodynamics documented a potential for first‐in‐human clinical evaluation (summarized in Roy, S. M., et al., 2019, J.Med.Chem., Drug Annotation: A Selective and Brain Penetrant p38αMAPK Inhibitor Candidate for Neurologic and Neuropsychiatric Disorders That Attenuates Neuroinflammation and Cognitive Dysfunction)ResultMW150 is a unique, orally bioavailable, stress kinase inhibitor that exhibits brain exposure and efficacy in diverse CNS disease models characterized by a neuroinflammation‐synaptic dysfunction axis. Promising results from ongoing studies suggest MW150 may be phase 2‐ready clinical asset available in Q3 2020: 1) phase 1a (SAD) and 1b (MAD) clinical trials; 2) six‐ and nine‐month preclinical toxicology; 3) commercial scale GMP clinical drug suitable for phase 2 and 3 clinical trials.ConclusionMW150 has the potential to provide a new therapeutic intervention mechanism for neurologic disease modification. There are no clinical trials of drugs with MW150’s unique profile of molecular recognition, pharmacological selectivity and safety.

AbstractIntroductionPRI‐002 is an orally available anti–amyloid beta (Aβ) prionic compound developed for direct disassembly of toxic Aβ oligomers relevant to Alzheimer's disease.MethodsTwo placebo‐controlled clinical phase I trials with oral dosing of PRI‐002 were conducted in healthy young subjects: A single ascending dose trial (4, 12, 36, 108, or 320 mg PRI‐002 or placebo) in 40 participants followed by a multiple ascending dose study with daily 160 mg PRI‐002 for 14 days or 320 mg for 28 days in 24 participants. The main objectives were safety, tolerability, and evaluation of pharmacokinetic (PK) parameters.ResultsPRI‐002 was safe and well tolerated after single and multiple oral administration up to the highest doses. PRI‐002 was absorbed rapidly and drug exposure increased proportional to dose. During repeated daily administration, the drug accumulated by a factor of about three. Steady‐state conditions were reached after 1 to 2 weeks.ConclusionsThe safety and PK results encourage further clinical development of PRI‐002.

The aim of this research is to test the ability of diffusion kurtosis imaging (DKI) to detect Parkinson´s disease-like pathology at an early stage when a neuroprotective treatment may still be effective.

Mitochondrial dysfunction is an early feature of Alzheimer's disease (AD) and may play an important role in the pathogenesis of disease. It has been shown that amyloid beta peptide (Aβ) and amyloid precursor protein (APP) interact with mitochondria contributing to the mitochondrial dysfunction in AD. Prevention of abnormal protein targeting to mitochondria can protect normal mitochondrial function, increase neuronal survival and at the end, ameliorate symptoms of AD and other neurodegenerative disorders. First steps of mitochondrial protein import are coordinated by molecular chaperones Hsp70 and Hsp90 that bind to the newly synthesized mitochondria‐destined proteins and deliver them to the protein import receptors on the surface of organelle. Here, we have described the development of a novel compound named GMP‐1 that disrupts interactions between Hsp70/Hsp90 molecular chaperones and protein import receptor Tom70. GMP‐1 treatment of SH‐SY5Y cells results in decrease in mitochondria‐associated APP and protects SH‐SY5Y cells from toxic effect of Aβ1‐42 exposure. Experiments in drosophila and mice models of AD demonstrated neuroprotective effect of GMP‐1 treatment, improvement in memory and behaviour tests as well as restoration of mitochondrial function.

It is intriguing that a rare, inherited lysosomal storage disorder Niemann-Pick type C (NPC) shares similarities with Alzheimer's disease (AD). We have previously reported an enhanced processing of β-amyloid precursor protein (APP) by β-secretase (BACE1), a key enzyme in the pathogenesis of AD, in NPC1-null cells. In this work, we characterized regional and temporal expression and processing of the recently identified BACE1 substrates seizure protein 6 (Sez6) and seizure 6-like protein (Sez6L), and APP, in NPC1-/- (NPC1) and NPC1+/+ (wt) mouse brains. We analysed 4-weeks old brains to detect the earliest changes associated with NPC, and 10-weeks of age to identify changes at terminal disease stage. Sez6 and Sez6L were selected due to their predominant cleavage by BACE1, and their potential role in synaptic function that may contribute to presentation of seizures and/or motor impairments in NPC patients. While an enhanced BACE1-cleavage of all three substrates was detected in NPC1 vs. wt-mouse brains at 4-weeks of age, at 10-weeks increased proteolysis by BACE1 was observed for Sez6L in the cortex, hippocampus and cerebellum of NPC1-mice. Interestingly, both APP and Sez6L were found to be expressed in Purkinje neurons and their immunostaining was lost upon Purkinje cell neurodegeneration in 10-weeks old NPC1 mice. Furthermore, in NPC1- vs. wt-mouse primary cortical neurons, both Sez6 and Sez6L showed increased punctuate staining within the endolysosomal pathway as well as increased Sez6L and BACE1-positive puncta. This indicates that a trafficking defect within the endolysosomal pathway may play a key role in enhanced BACE1-proteolysis in NPC disease. Overall, our findings suggest that enhanced proteolysis by BACE1 could be a part of NPC disease pathogenesis. Understanding the basic biology of BACE1 and the functional impact of cleavage of its substrates is important to better evaluate the therapeutic potential of BACE1 against AD and, possibly, NPC disease.

Development of new drugs for treatment of Alzheimer’s disease (AD) requires valid paradigms for testing their efficacy and sensitive tests validated in translational research.

DKI by measuring non-Gaussian diffusion may better characterize the microstructural brain changes as compared to traditional DTI. The aim was to evaluate the capability of DKI for detecting the microstructural changes induced by alpha-synuclein accumulation in TNWT-61 mice using the tract based spatial statistics (TBSS) and region of interest (ROI) analyses. Fourteen month old TNWT-61 mice and wild-type (WT) littermates underwent DKI scanning using 9.4 Tesla MRI system in vivo. TBSS and ROI analysis was performed to detect the changes in white and gray matter in TNWT-61 and WT mice. Immunohistochemistry for alpha-synuclein was performed in 5 TNWT-61 mice and correlated with DKI findings. The principle findings of this study were increase in mean kurtosis and decrease in mean diffusivity in thalamus, sensorimotor cortex, hippocampus, external capsule and basolateral amygdaloid nucleus in 14 month TNWT-61 mice as compared to WT littermates. We also found significant correlations between alpha-synuclein accumulation and increase in kurtosis and decrease in diffusivity in the thalamus. Our results reveal that DKI is sensitive in detecting microstructural changes due to alpha-synuclein accumulation in both GM and WM. These findings suggest that in PD patients DKI should be preferred to routine DTI despite a longer acquisition protocol.

Basel • Freiburg • Paris • London • New York • New Delhi • Bangkok • Beijing • Tokyo • Kuala Lumpur • Singapore • Sydney S. Karger Medical and Scientific Publishers Basel • Freiburg • Paris • London • New York • Bangalore • Bangkok • Shanghai • Singapore • Tokyo • Sydney Disclaimer The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publisher and the editor(s). The appearance of advertisements in the journal is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements. Drug Dosage The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any change in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug. All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher or, in the case of photocopying, direct payment of a specified fee to the Copyright Clearance Center (see ‘General Information’). © Copyright 2013 by S. Karger AG, P.O. Box, CH–4009 Basel (Switzerland) e-ISBN 978–3–318-02391-6 E-Mail karger@karger.com www.karger.com Vol. 11, Suppl. 1, 2013

The adamantane moiety is the structural backbone of numerous compounds and its discovery launched a new field of chemistry studying the approaches to the synthesis as well as the physicochemical and biological properties of organic polyhedral compounds with practical application in the pharmaceutical industry. Adamantane derivatives have proven to be very potent compounds in a wide range of applications from systemic to topical therapy. This review summarizes the currently available adamantane derivatives in clinical practice (amantadine, memantine, rimantadine, tromantadine, adapalene, saxagliptin, vildagliptin), focusing on mechanisms of action, pharmacokinetics, pharmacodynamics and clinical trials. The adamantane-based compounds presented in this manuscript have been approved for a wide spectrum of indications (antivirals, antidiabetics and against Alzheimer's and Parkinson's disease). Each of the compounds proved to be of vital importance in their therapeutic indication for numerous patients worldwide. This review also considers the mechanisms of side effects to deliver a complete perspective on current treatment options.

Neurofibrillary tangles (NFT) are the second hallmark of Alzheimer’s disease (AD) and are well correlated to disturbances in cognition. The rTg4510 mouse, a model of tauopathy, overexpresses P301L mutant human Tau in the forebrain under control of a tetracycline tans-acting element (TET-Off). The mice develop neurobrillary pathology already at an age of 2,5 to 3 months, and show progressive gross brain atrophy and significant neuronal loss in hippocampal structures. The study investigated effects of suppression of transgene expression by doxycycline (Doxy) feeding on complex behavioral readouts and correlation to changes in brain pathology. Feeding of mice with Doxy (200 ppm) started at an age of 2.5 months and was maintained until an age of 6 m. The proprietary Cube technology was used to document spontaneous behavior, gait, motor function, but also social interaction, day/ night activity and cognition. Effects on NFTs and brain atrophy were measured using quantitative histological methods, the influence on brain inflammation markers was examined using real time PCR. Transgene suppression over 2,5 months is decreasing tau expression significantly, resultíng in normalization of T-maze performance, but also modulation of practically all disturbed behavioral features that were investigated using SmartCube, NeuroCube and PhenoCube, including motor function, rearing, hyperactivity and social behavior. Beside known effects on brain pathology, Doxy normalizes expression of different pro-inflammatory markers in the mouse brain, which could be in connection to progressive brain atrophy. The data show that exposure to Doxy results in at least a partial reversal of the deficits in the rTG4510mice which were recorded using unique, high-through-put behavioral methods, which correlates to a significant decrease in markers of neuro-inflammation and expected reduction of NFT pathology, indicating that abnormally processed tau protein is essential for these disturbances. Shutting down transgene expression by Doxy is a useful benchmarking for preclinical treatment trials for drugs addressing tau pathology.

Tg2576 mice are one of the standard models for AD research. The APP/PS1 mice are produced by cross-breeding them with PS1 tg mice. PS1 mutation changes processing of APP, increasing the proportion of pro-aggregatory ABeta42, accelerating formation of plaque pathology and functional deficits. It is first time that both models were compared using proprietary, sensitive behavioral tests that may have the capability to increase predictive drug testing in AD animals models. It was of interest to explore to what extent differences in behavioral performance between both mouse lines is reflected by differences in AD-like brain pathology. This is important also for interpretation of results from treatment trials. Female 13 and 52 weeks old tg2576 and APP/PS1 mice were investigated using SmartCube (spontaneous behavior), NeuroCube (Measurement of gait and motor function) and the PhenoCube (social interaction, day/ night activity and cognition) Systems. At the end of the experiments mice brains were investigated for differences in plaque pathology, astro-glioses and micro-glia activation using quantitative immunohistochemistry. In all behavioral examinations was a clear difference to age matched wt-controls which increased with age. Differences between the two tg-mouse lines are smaller than the distinction from the controls. In general APP/PS1 mice perform worse than the tg 2576 mice, except in the investigation of social interaction, where tg 2576 mice progress with increased interaction, but the phenotype of the APPPS1 mice is closer to normal situation with increasing age. Detailed immune-histochemical examination is trying to connect this to differences in brain pathology. The data show that also in this new, very detailed behavioral tests there is a clear distinction between the two genotypes, which may relate mainly to differences in APP processing due to the PS1 mutation. The relationship between behavior and findings in brain IHC suggest also the importance of choosing the right animal model for efficacy testing.

Processing of the amyloid precursor protein (APP) and amyloid beta (Aβ) has been for decades in the center of Alzheimer's disease (AD) research. Beside many other variables, lipids, especially cholesterol and its derivatives, are discussed to contribute to AD pathogenesis. Several studies show that cholesterol affects APP metabolism. Also the converse mechanism, the direct influence of Aβ on cholesterol metabolism, has been described. To further investigate this crosstalk between cholesterol- and APP metabolism, a high-fat feeding study was conducted with animals overexpressing human APPSL and/or human ApoB-100. The impact of diet and genotype on cerebral cholesterol metabolism and content as well as spatial learning and memory was examined. While behavioral performance was not influenced by this high fat diet (HFD), reduction of cortical free cholesterol levels and mRNA expression patterns under normal diet and HFD conditions in human APPSL overexpressing mice argue for an important role of APP in cerebral lipid metabolism. From our results we conclude that increased APP metabolism in ApoBxAPP and APPSL mice induces mechanisms to reduce free cholesterol levels.

Diffusion kurtosis imaging (DKI) by measuring non‐Gaussian diffusion allows an accurate estimation of the distribution of water molecule displacement and may correctly characterize microstructural brain changes caused by neurodegeneration. The aim of this study was to evaluate the ability of DKI to detect changes induced by α‐synuclein (α‐syn) accumulation in α‐syn over‐expressing transgenic mice (TNWT‐61) in both gray matter (GM) and white matter (WM) using region of interest (ROI) and tract‐based spatial statistics analyses, respectively, and to explore the relationship between α‐syn accumulation and DKI metrics in our regions of interest. Fourteen‐month‐old TNWT‐61 mice and wild‐type (WT) littermates underwent in vivo DKI scanning using the Bruker Avance 9.4 Tesla magnetic resonance imaging system. ROI analysis in the GM regions substantia nigra, striatum, hippocampus, sensorimotor cortex, and thalamus and tract‐based spatial statistics analysis in WM were performed. Immunohistochemistry for α‐syn was performed in TNWT‐61 mice and correlated with DKI findings. We found increased kurtosis and decreased diffusivity values in GM regions such as the thalamus and sensorimotor cortex, and in WM regions such as the external and internal capsule, mamillothalamic tract, anterior commissure, cingulum, and corpus callosum in TNWT‐61 mice as compared to WT mice. Furthermore, we report for the first time that α‐syn accumulation is positively correlated with kurtosis and negatively correlated with diffusivity in the thalamus. The study provides evidence of an association between the amount of α‐syn and the magnitude of DKI metric changes in the ROIs, with the potential of improving the clinical diagnosis of Parkinson's disease.