D. Van Dam

Partial cure of established disease in an animal model of metachromatic leukodystrophy after intracerebral adeno-associated virus-mediated gene transfer

Metachromatic leukodystrophy (MLD) is a lysosomal storage disease caused by genetic deficiency of arylsulfatase A (ARSA) enzyme. Failure in catalyzing the degradation of its major substrate, sulfatide (Sulf), in oligodendrocytes and Schwann cells leads to severe demyelination in the peripheral (PNS) and central nervous system (CNS), and early death of MLD patients. The ARSA knockout mice develop a disease that resembles MLD but is milder, without significant demyelination in the PNS and CNS. We showed that adeno-associated virus serotype 5-mediated gene transfer in the brain of ARSA knockout mice reverses Sulf storage and prevents neuropathological abnormalities and neuromotor disabilities when vector injections are performed at a pre-symptomatic stage of disease. Direct injection of viral particles into the brain of ARSA knockout mice at a symptomatic stage results in sustained expression of ARSA, prevention of Sulf storage and neuropathological abnormalities. Despite these significant corrections, the treated mice continue to develop neuromotor disability. We show that more subtle biochemical abnormalities involving gangliosides and galactocerebroside are in fact not corrected.

Ibuprofen modifies cognitive disease progression in an Alzheimer’s mouse model

Prolonged use of non-steroidal anti-inflammatory drugs (NSAIDs) may reduce the risk of developing Alzheimer’s disease (AD) and delay disease onset. Negative results of clinical AD trials were rationalised by the discovery that certain NSAIDs reduce amyloid-β 1—42 (Aβ1— 42) peptide production, the proposed central culprit in AD pathophysiology and main constituent of amyloid plaques, whereas other compounds do not affect Aβ levels. Latter observations motivated further in-vitro and in-vivo research regarding the applicability of NSAIDs in treating and/or preventing AD. We used the age-dependent cognitive decline in the APP23 transgenic mouse model for AD to evaluate disease-modifying efficacy of chronic ibuprofen treatment at the cognitive level. At age 6 weeks, heterozygous APP23 mice and control littermates were subcutaneously implanted with osmotic pumps delivering saline or ibuprofen (50 mg/kg daily). After 2 months of treatment, a 3-week washout period prevented bias from potential symptomatic effects before cognitive evaluation commenced. Ibuprofen-treated APP23 mice performed significantly better than their sham-treated counterparts and almost attained the same level of performance as control animals on a complex visual-spatial learning task. This study clearly reports disease-modifying efficacy of ibuprofen at the cognitive level in transgenic mice modelling AD.

Prevalence and incidence of dementia among 75–80-year-old community-dwelling elderly in different districts of Antwerp, Belgium: The Antwerp Cognition (ANCOG) Study

OBJECTIVE To analyse the prevalence and incidence of dementia in a population of community-dwelling elderly (aged 75-80), living in socio-economically differing districts of Antwerp (Belgium), taking into account possible gender and educational differences. METHODS A longitudinal cohort study (N=825) with a 3-year follow-up period (N=363). The Mini Mental State Examination (MMSE) was used as a primary screen of cognitive functioning. Scoring 21 or below led to a second phase examination by a neurologist, including the CAMDEX-R-N and a neurological examination, to provide a tentative aetiological diagnosis of dementia. These procedures were conducted annually during a 3-year follow-up period. RESULTS In accordance with international literature, the overall prevalence rate of dementia was 8.7%. The cumulative incidence rate (IR) of dementia was 36.60 per 1000Py with annual IRs ranging from 34.39 over 35.16 to 49.04 per 1000Py. Dementia of the Alzheimer type (DAT) was the most occurring prevalent and incident cause. Women appeared to be at higher risk and the occurrence of cognitive deterioration was more prominent in districts with lower socio-economic status, possibly related to a lower education level. CONCLUSION We demonstrate dementia is a considerable health problem in an urban Belgian population of community-dwelling elderly aged between 75 and 80 years old. In order to prepare health care and social security systems for the future management of dementia, proper epidemiological insight into the current and future magnitude of the burden of dementia, taking into account socio-economic differences, to which this study contributes, are required.

Regional distribution of biogenic amines, amino acids and cholinergic markers in the CNS of the C57BL=6 strain

Summary.A reliable extrapolation of neurochemical alterations from a mouse model to human metabolic brain disease requires knowledge of neurotransmitter levels and related compounds in control mouse brain. C57BL/6 is a widely used background strain for knockout and transgenic mouse models. A prerequisite for reliable extrapolation from mouse brain to the human condition is the existence of analogous distribution patterns of neurotransmitters and related compounds in control mouse and human brain. We analysed regional distribution patterns of biogenic amines, neurotransmitter and non-neurotransmitter amino acids, and cholinergic markers. Distribution patterns were compared with known neurotransmitter pathways in human brain. The present study provides a reference work for future analyses of neurotransmitters and related compounds in mouse models bred in a C57BL/6 background strain.

Behavioural characterization of AnkyrinG deficient mice, a model for ANK3 related disorders

ABSTRACT ANK3 encodes AnkyrinG (AnkG), a member of the Ankyrin family that is expressed in several different isoforms in many tissues. A unique serine‐rich domain and tail domain in the two largest isoforms of AnkG (270 and 480 kDa), restrict AnkG to the axon initial segment and nodes of Ranvier of myelinated neurons. At these sites, AnkG is a master regulator, coordinating the strict clustering of components necessary for proper action potential initiation and propagation along the axon. These components include voltage‐gated sodium channels, potassium channels and members of the L1 cell adhesion molecule family. Genetic variation in the ANK3 gene has been linked to a range of neuropsychiatric and neurodevelopmental disorders in human, including schizophrenia, bipolar disorder, intellectual disability and autism spectrum disorders. Here, we study the effect of reduced expression of the large isoforms of Ank3 on cognition and behaviour using a heterozygous knockout mouse model. In three independent behavioural tests, being the open field test, elevated plus maze and social interaction test, we found evidence for increased anxiety in our Ank3 mouse model. Besides, we observed specific neuroanatomical defects in heterozygous knockout mice, including a smaller cingulate cortex, granular retrosplenial cortex, primary motor cortex and fimbria of the hippocampus.

NAP has no effect on spatial memory after short-term treatment in advanced stage Alzheimer's disease mouse model.

NAPVSIPQ (NAP) is a small, active fragment of activity-dependent neuroprotective protein that has neuroprotective and memory enhancing properties at very low concentrations. Previous research demonstrated that 1-2 weeks of treatment provided memory enhancing effects in normal middle-aged and cholinergically lesioned rats. Improvement in cognitive performance was shown in 12-month-old C57Bl6/J mice after 10 days of oral treatment with D-NAP and D-SALLRSIPA. Additionally, NAP-related cognitive benefits on spatial memory were observed in a 3xTg Alzheimer mouse model after 6 months of chronic administration at a moderate stage of disease. In this study, the potential memory enhancing effect of NAP was investigated using the APP23 transgenic mouse model for Alzheimers disease. Twelve-month-old male heterozygous APP23 mice and their wild-type control littermates were intraperitoneally injected with 0.3 microg NAP/g body weight or with saline vehicle for 22 consecutive days. Cognitive performance training in the Morris Water Maze (MWM) started on day 8 of treatment. The internal validity of our study was demonstrated by the fact that the APP23 mice performed significantly worse in the MWM than wild-type animals. Treatment with NAP, however, did not exert any significant effects on MWM performance. Although we failed to show significant memory enhancing effects in this study, NAP might be a promising peptide for disease-modifying therapy in neurodegenerative disease, but short-term effects are probably not to be expected. Also, most likely, treatment should start in an early stage, i.e. before full-blown pathology is eminent, and the necessary treatment period should enclose several months.

The translaminar pressure difference as an index for neurotoxic burden in the anterior part of the optic nerve

The translaminar pressure difference as an index for neurotoxic burden in the anterior part of the optic nerve