Mickael Audrain

Viral gene transfer of APPsα rescues synaptic failure in an Alzheimer’s disease mouse model

Alzheimer’s disease (AD) is characterized by synaptic failure, dendritic and axonal atrophy, neuronal death and progressive loss of cognitive functions. It is commonly assumed that these deficits arise due to β-amyloid accumulation and plaque deposition. However, increasing evidence indicates that loss of physiological APP functions mediated predominantly by neurotrophic APPsα produced in the non-amyloidogenic α-secretase pathway may contribute to AD pathogenesis. Upregulation of APPsα production via induction of α-secretase might, however, be problematic as this may also affect substrates implicated in tumorigenesis. Here, we used a gene therapy approach to directly overexpress APPsα in the brain using AAV-mediated gene transfer and explored its potential to rescue structural, electrophysiological and behavioral deficits in APP/PS1∆E9 AD model mice. Sustained APPsα overexpression in aged mice with already preexisting pathology and amyloidosis restored synaptic plasticity and partially rescued spine density deficits. Importantly, AAV-APPsα treatment also resulted in a functional rescue of spatial reference memory in the Morris water maze. Moreover, we demonstrate a significant reduction of soluble Aβ species and plaque load. In addition, APPsα induced the recruitment of microglia with a ramified morphology into the vicinity of plaques and upregulated IDE and TREM2 expression suggesting enhanced plaque clearance. Collectively, these data indicate that APPsα can mitigate synaptic and cognitive deficits, despite established pathology. Increasing APPsα may therefore be of therapeutic relevance for AD.

Cholesterol 24-hydroxylase defect is implicated in memory impairments associated with Alzheimer-like Tau pathology

Alzheimers disease (AD) is characterized by both amyloid and Tau pathologies. The amyloid component and altered cholesterol metabolism are closely linked, but the relationship between Tau pathology and cholesterol is currently unclear. Brain cholesterol is synthesized in situ and cannot cross the blood-brain barrier: to be exported from the central nervous system into the blood circuit, excess cholesterol must be converted to 24S-hydroxycholesterol by the cholesterol 24-hydroxylase encoded by the CYP46A1 gene. In AD patients, the concentration of 24S-hydroxycholesterol in the plasma and the cerebrospinal fluid are lower than in healthy controls. The THY-Tau22 mouse is a model of AD-like Tau pathology without amyloid pathology. We used this model to investigate the potential association between Tau pathology and CYP46A1 modulation. The amounts of CYP46A1 and 24S-hydroxycholesterol in the hippocampus were lower in THY-Tau22 than control mice. We used an adeno-associated virus (AAV) gene transfer strategy to increase CYP46A1 expression in order to investigate the consequences on THY-Tau22 mouse phenotype. Injection of the AAV-CYP46A1 vector into the hippocampus of THY-Tau22 mice led to CYP46A1 and 24S-hydroxycholesterol content normalization. The cognitive deficits, impaired long-term depression and spine defects that characterize the THY-Tau22 model were completely rescued, whereas Tau hyperphosphorylation and associated gliosis were unaffected. These results argue for a causal link between CYP46A1 protein content and memory impairments that result from Tau pathology. Therefore, CYP46A1 may be a relevant therapeutic target for Tauopathies and especially for AD.

Interleukin-2 improves amyloid pathology, synaptic failure and memory in Alzheimer’s disease mice

Interleukin-2 (IL-2)-deficient mice have cytoarchitectural hippocampal modifications and impaired learning and memory ability reminiscent of Alzheimers disease. IL-2 stimulates regulatory T cells whose role is to control inflammation. As neuroinflammation contributes to neurodegeneration, we investigated IL-2 in Alzheimers disease. Therefore, we investigated IL-2 levels in hippocampal biopsies of patients with Alzheimers disease relative to age-matched control individuals. We then treated APP/PS1ΔE9 mice having established Alzheimers disease with IL-2 for 5 months using single administration of an AAV-IL-2 vector. We first found decreased IL-2 levels in hippocampal biopsies of patients with Alzheimers disease. In mice, IL-2-induced systemic and brain regulatory T cells expansion and activation. In the hippocampus, IL-2 induced astrocytic activation and recruitment of astrocytes around amyloid plaques, decreased amyloid-β42/40 ratio and amyloid plaque load, improved synaptic plasticity and significantly rescued spine density. Of note, this tissue remodelling was associated with recovery of memory deficits, as assessed in the Morris water maze task. Altogether, our data strongly suggest that IL-2 can alleviate Alzheimers disease hallmarks in APP/PS1ΔE9 mice with established pathology. Therefore, this should prompt the investigation of low-dose IL-2 in Alzheimers disease and other neuroinflammatory/neurodegenerative disorders.

Is it time to rethink the Alzheimer's disease drug development strategy by targeting its silent phase?

Alzheimer’s disease (AD) is the most frequent cause of dementia in the western world. In clinical terms, AD is characterized by progressive cognitive decline that usually begins with memory impairment. As the disease progresses, AD inevitably affects all intellectual functions including executive functions, leading to complete dependence for basic activities of daily life and premature death. Around 47 million people live with AD worldwide and the number of patients is estimated to surge to 130 million in 2050 if we don’t find a cure (Prince et al., 2015). By 2018 it will become a trillion-dollar disease and this economic cost inflicts a significant financial burden on individuals and families. In the US, out-of-pocket costs for families affected by Alzheimer’s account for more than

59. APPsα Gene Therapy for Alzheimer's Disease

8,000 on average each year. It makes Alzheimer’s disease the most expensive illness for families during the last five years of life (Kelley et al., 2013). Unfortunately, there are no effective treatments against AD, although some drugs can alleviate the symptoms associated with it.

Gene transfer of both app and ps1 induces hippocampal impairments close to human early phases of Alzheimer’s disease

Alzheimers disease (AD) is characterized by synaptic failure, dendritic and axonal atrophy, neuronal death and progressive loss of cognitive functions asocieted with β-amyloid accumulation and neurofibrillary tangles of phosphorylated Tau protein. Increasing evidence indicates that loss of physiological APP functions mediated predominantly by neurotrophic APPsα produced in the non-amyloidogenic α-secretase pathway may contribute to AD pathogenesis. We used an AAV vector to directly overexpress APPsa in the brain and explored its potential to rescue structural, electrophysiological and behavioral deficits in APP/PS1ΔE9 AD mouse model. Sustained APPsα overexpression in aged mice with already preexisting pathology and amyloidosis restored synaptic plasticity and rescued spine density deficits. Importantly, AAV-APPsα treatment also resulted in a functional rescue of spatial memory. A significant reduction of both toxic soluble β42 and plaque load was evidenced. APPsα induced the recruitment of microglia with ramified morphology towards plaques and upregulated IDE and TREM2 expression suggesting enhanced plaque clearance. APPsα overexpression in the brain using an AAV vector improves synaptic and cognitive deficits, despite established pathology and may be of therapeutic relevance for AD.

Hippocampal CYP46A1 overexpression is beneficial in rodent models of Alzheimer’s disease

hypothesize regional specific interactions between biomarkers. Methods: McGill-R-Thy1-APP rat (n1⁄49) and wild type (wt; n1⁄412) had [F]FDG and structural MRIs scans at 11-month (baseline) and 16-month (follow-up). Structural images were acquired using a Bruker 70/30USR Biospect MRI (FISP; TE/TR: 2.5/ 5.0ms; FOV: 3.6cm; isotropic 250um voxels; 8 angles). Voxelbased morphometry was performed to obtain longitudinal deforma-

AAV-CYP46A1 BRAIN DELIVERY MITIGATES ALZHEIMER’S DISEASE: FROM MOUSE MODELS TO NON-HUMAN PRIMATES

for the gamma. Conclusions:Predicted treatment effects based on normal or chi-square distributions may show greater progression and less variability than those based on gamma distributions. While the results are similar between normal and chi-square distributions, the latter may be preferred on statistical and clinical grounds: 1) it has fewer parameters to evaluate; 2) it allows for a more realistic distribution of declines over time, where a few patients may fail or worsen more markedly than would be predicted by the former.