Bruno Bergmans

MicroRNA regulation of Alzheimer's Amyloid precursor protein expression.

Gene dosage effects of Amyloid precursor protein (APP) can cause familial AD. Recent evidence suggest that microRNA (miRNA) pathways, implicated in gene transcriptional control, could be involved in the development of sporadic Alzheimers disease (AD). We therefore investigated whether miRNAs could participate in the regulation of APP gene expression. We show that miRNAs belonging to the miR-20a family (that is, miR-20a, miR-17-5p and miR-106b) could regulate APP expression in vitro and at the endogenous level in neuronal cell lines. A tight correlation between these miRNAs and APP was found during brain development and in differentiating neurons. We thus identify miRNAs as novel endogenous regulators of APP expression, suggesting that variations in miRNA expression could contribute to changes in APP expression in the brain during development and disease. This possibility is further corroborated by the observation that a statistically significant decrease in miR-106b expression was found in sporadic AD patients.

γ-secretases: from cell biology to therapeutic strategies

Presenilins form the catalytic part of the gamma-secretases, protein complexes that are responsible for the intramembranous cleavage of transmembrane proteins. The presenilins are involved in several biological functions, but are best known for their role in the generation of the beta-amyloid (Abeta) peptide in Alzheimers disease and are therefore thought to be important drug targets for this disorder. Mutations in the presenilin genes cause early-onset familial Alzheimers disease, but mutation carriers have substantial phenotypic heterogeneity. Recent evidence implicating presenilin mutations in non-Alzheimers dementias, including frontotemporal dementia and Lewy body dementia, warrants further investigation. An increased understanding of the diversity of the molecular cell biology of the gamma-secretase complex and the effects of clinical mutations in the presenilin genes might help pave the way for improved development of drugs that are designed to target gamma-secretase enzymatic activity in Alzheimers disease and potentially in other neurological diseases.

Neurons generated from APP/APLP1/APLP2 triple knockout embryonic stem cells behave normally in vitro and in vivo: lack of evidence for a cell autonomous role of the amyloid precursor protein in neuronal differentiation.

Alzheimers disease amyloid precursor protein (APP) has been implicated in many neurobiologic processes, but supporting evidence remains indirect. Studies are confounded by the existence of two partially redundant APP homologues, APLP1 and APLP2. APP/APLP1/APLP2 triple knockout (APP tKO) mice display cobblestone lissencephaly and are perinatally lethal. To circumvent this problem, we generated APP triple knockout embryonic stem (ES) cells and differentiated these to APP triple knockout neurons in vitro and in vivo. In comparison with wild‐type (WT) ES cell‐derived neurons, APP tKO neurons formed equally pure neuronal cultures, had unaltered in vitro migratory capacities, had a similar acquisition of polarity, and were capable of extending long neurites and forming active excitatory synapses. These data were confirmed in vivo in chimeric mice with APP tKO neurons expressing the enhanced green fluorescent protein (eGFP) present in a WT background brain. The results suggest that the loss of the APP family of proteins has no major effect on these critical neuronal processes and that the apparent multitude of functions in which APP has been implicated might be characterized by molecular redundancy. Our stem cell culture provides an excellent tool to circumvent the problem of lack of viability of APP/APLP triple knockout mice and will help to explore the function of this intriguing protein further in vitro and in vivo. STEM CELLS 2010;28:399–406

Core auditory processing deficits in primary progressive aphasia

The extent to which deficits in non-verbal auditory processing contribute to the clinical phenotype of primary progressive aphasia (PPA) is unclear. Grube et al. reveal impairments in processing the timing of brief sequences of non-linguistic stimuli, particularly in the non-fluent variant, indicative of a core central auditory impairment in PPA.

A Retrospective Belgian Multi-Center MRI Biomarker Study in Alzheimer's Disease (REMEMBER).

Background: Magnetic resonance imaging (MRI) acquisition/processing techniques assess brain volumes to explore neurodegeneration in Alzheimer’s disease (AD). Objective: We examined the clinical utility of MSmetrix and investigated if automated MRI volumes could discriminate between groups covering the AD continuum and could be used as a predictor for clinical progression. Methods: The Belgian Dementia Council initiated a retrospective, multi-center study and analyzed whole brain (WB), grey matter (GM), white matter (WM), cerebrospinal fluid (CSF), cortical GM (CGM) volumes, and WM hyperintensities (WMH) using MSmetrix in the AD continuum. Baseline (n = 887) and follow-up (FU, n = 95) T1-weighted brain MRIs and time-linked neuropsychological data were available. Results: The cohort consisted of cognitively healthy controls (HC, n = 93), subjective cognitive decline (n = 102), mild cognitive impairment (MCI, n = 379), and AD dementia (n = 313). Baseline WB and GM volumes could accurately discriminate between clinical diagnostic groups and were significantly decreased with increasing cognitive impairment. MCI patients had a significantly larger change in WB, GM, and CGM volumes based on two MRIs (n = 95) compared to HC (FU>24months, p = 0.020). Linear regression models showed that baseline atrophy of WB, GM, CGM, and increased CSF volumes predicted cognitive impairment. Conclusion: WB and GM volumes extracted by MSmetrix could be used to define the clinical spectrum of AD accurately and along with CGM, they are able to predict cognitive impairment based on (decline in) MMSE scores. Therefore, MSmetrix can support clinicians in their diagnostic decisions, is able to detect clinical disease progression, and is of help to stratify populations for clinical trials.

Pearls & Oy-sters: Visual agnosia An overlooked cortical sign

We report a 77-year-old patient with visual agnosia as a cortical sign of neurodegenerative disease.

EHMTI-0394. Predictive parameters for the effect of botulinum toxin infiltrations in chronic migraine

Since the PREEMPT trials botulinum toxin infiltrations have become mainstay treatments for chronic migraine. Although not reimbursed in Belgium, botulinum toxin infiltrations can be a viable option for refractory chronic migraine patients in whom previous oral treatments have failed.