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J O U R N A L R E V I E W SEditor’s ChoiceA mutation for protectionagainst Alzheimer’s diseaseThe perceived importance of amyloid in the pathogenesisof Alzheimer’s disease has fluctuated in thelast 30 years. Deposition of amyloid is a pathologicalhallmark of the disease and suggests a central role forthe protein in the disease. The association of Down’ssyndrome, trisomy 21, with Alzheimer’s made theAmyloid Precursor Protein (APP) gene on chromosome21 an obvious candidate gene for autosomaldominant Alzheimer’s disease. Initial genetic linkagestudies excluded APP as the site of the causativemutation. The subsequent realisation that Alzheimer’sdisease might be caused by more than one gene byJohn Hardy’s group led to a re-examination of linkageresults and the discovery that APP mutations cancause autosomal dominant Alzheimer’s disease. Over20 further pathological mutations in the APP genehave been described, however, APP mutations provedcomparatively rare. Other genes, Presenilin 1 andAPOE, stole much of the limelight. In Alzheimer’sdisease drug development, there was a clear rationaleto developing treatments that influenced amyloidmetabolism or deposition. These treatments havebeen developed and shown initial promise but, so far,have disappointed.This paper is another step in the Alzheimer/amyloid story. Jonsson and colleagues utilised wholegenome data from over 1500 Icelanders to look forsequence changes in the APP gene. They identified acoding mutation (A673T) which confers protectionagainst Alzheimer’s disease in their cohort and showthat this mutation reduces the production ofamyloidogenic peptides in vitro. Their controls wereelderly (over 85 years of age) and had passed acognitive assessment. Jonsson and colleagues foundthat the A673T mutation was also rarer in patientswith less specific “cognitive decline”. The results lookrobust and there seems little reason to suppose thatthey will not apply to a wider population thanIceland, but this remains to be shown. 0.6% of thecontrol Icelandic population carry the mutation sothe effect is significant although the protective allelemay be rarer in other populations. This discovery willalso encourage therapeutic approaches aimed ataltering APP metabolism.It is not surprising that these results apply also topatients with cognitive decline not diagnosed withAD. It highlights the spectrum that exists between the“normal” decline in memory with age, amnestic MildCognitive Impairment and Alzheimer’s disease. Theresult supports the theory that very mild Alzheimer’spathology may be responsible for minor cognitiveproblems as people age. This observation highlightsthe question that already troubles Alzheimer specialists:of when a minor cognitive problem becomes adisease.– Dr Jeremy Brown, Addenbrooke’s Hospital and QueenElizabeth Hospital, King’s Lynn.Jonsson et al. A mutation in APP protects againstAlzheimer's disease and age-related cognitive decline.Nature: 488, 96–99. Date published: (02 August 2012)miRNA and ASO –The initial approachto treating geneticdiseases in a new wayOne of the holy grails of treating geneticdisorders of the CNS is to target theabnormal gene itself and by so doingeffect a cure without having to worryabout off target effects. There have beentwo recent papers which are worth highlightingin this regard – one using amicroRNA approach, the other an antisenseoligonucleotide (ASO) strategyand both involving autosomal dominanttrinucleotide repeat disorders.In the first paper by Miyazaki et al inNature Medicine (with a wonderfullyclear News and Views commentary on itby Christopher Pearson), they concentratedon spinal bulbar muscular atrophy(SBMA) which is a slowly progressivelower motor neuron disorder of men. Thedisease is characterised by a CAG expansionin the androgen receptor, whichthen causes motor neuronal cell dysfunctionand death through translocation ofthe mutant receptor within the cell. Thishas in the past led to attempts to blocktranslocation using anti-androgen agents,although as a clinical therapy this createsobvious problems. In this new paper theauthors looked at a transgenic model ofthis condition and found that oneendogenous microRNAs in particular(the imaginatively named miRNA-196a)was upregulated and that by overexpressingit they could slow down thedisease process. This they did using anAAV delivery system that selectivelytargeted the motoneurons. They thenshowed that miR-196a mediated itseffects on the mutant receptor through aprotein that is involved with mRNAprocessing (CELF2). This beautiful workshows how miRNAs are coming of agenot only in terms of how they regulatenetworks of intracellular processes buthow they can be recruited for treatingdisease.In the second study the disease underattack is Huntington’s disease, which has itsCAG repeat in exon 1 of the huntingtin(htt) gene. This gene product causes extensivecell loss in the CNS but typically notuntil patients are in their 40s, althoughexactly when the disease process beginsrelative to clinical expression remains asubject of great interest (see TRACK-HDand PREDICT-HD studies). Obviouslybeing able to switch off the mutant gene(mthtt) whilst leaving the normal htt to doits job has proven difficult, as has gettingthe silencing agent for the mutant htt in allcells for long period of times. This last pointin particular has vexed the field but arecent paper by Kordasiewicz et al inNeuron (again accompanied by a lovelyPreview by Lu and Yang) suggests that thismight not be necessary as they showedthat transiently knocking down mthttcould have long lasting benefits in animalmodels of disease. This implies that stoppingthe production of mthtt even if onlyfor a short time may allow the cell torecover, regroup and fight another day, andthus whilst repeated injections of ASOsmay be required, the frequency of administrationmay be less than once thought.These papers highlight once more theskill of researchers to get to the heart ofdisease, and their ingenuity in how to dothis. Obviously the challenge still remainsas to how one can translate such findingsinto a much larger, longer living humanpatient – but slowly we are movingtowards therapies that seek to trulyswitch off disease causing genes andtheir products.– Roger Barker, Cambridge Centre for BrainRepair.Pearson CE. Co-opting endogenousmicroRNAs for therapy.NATURE MEDICINE 2012;18:1011-2.Miyazaki Y, Adachi H, Katsuno M et al.Viral delivery of miR-196a amelioratesthe SBMA phenotype via the silencing ofCELF2.NATURE MEDICINE 2012;18:1136-1141.X-H Lu & X.W Yang. “Huntingtin Holiday”:progress toward an antisense therapy forHuntington’s disease.NEURON 2012;74:964-6.Kordasiewicz HB, Stanek LM, Wancewicz EVet al. Sustained Therapeutic Reversal ofHuntington's Disease by TransientRepression of Huntingtin Synthesis.NEURON 2012;74:1031-44.Intramuscularmidazolam for statusepilepticusLarge studies of status epilepticus whichchange practice are hard to come bybut this is one such. The study comparedthe outcome of treatment of statusepilepticus with IM midazolam and IVlorazepam, which has been the goldstandard since 1998. This massive effortincluded 3114 paramedics and 79 hospitals.Children estimated to be over 13Kgand adults were included and weretreated if convulsive seizures had beencontinuing for over five minutes. Patientswere excluded with major trauma, hypoglycaemia,cardiac arrest or HR VOLUME 12 NUMBER 4 > SEPTEMBER/OCTOBER 2012 > 37