title: Neuroinflammation and neuronal loss precede Aβ plaque deposition in the hAPP-J20 mouse model of Alzheimer's disease.
abstract: Recent human trials of treatments for Alzheimer's disease (AD) have been largely unsuccessful, raising the idea that treatment may need to be started earlier in the disease, well before cognitive symptoms appear. An early marker of AD pathology is therefore needed and it is debated as to whether amyloid-βAβ? plaque load may serve this purpose. We investigated this in the hAPP-J20 AD mouse model by studying disease pathology at 6, 12, 24 and 36 weeks. Using robust stereological methods, we found there is no neuron loss in the hippocampal CA3 region at any age. However loss of neurons from the hippocampal CA1 region begins as early as 12 weeks of age. The extent of neuron loss increases with age, correlating with the number of activated microglia. Gliosis was also present, but plateaued during aging. Increased hyperactivity and spatial memory deficits occurred at 16 and 24 weeks. Meanwhile, the appearance of plaques and oligomeric Aβ were essentially the last pathological changes, with significant changes only observed at 36 weeks of age. This is surprising given that the hAPP-J20 AD mouse model is engineered to over-expresses Aβ. Our data raises the possibility that plaque load may not be the best marker for early AD and suggests that activated microglia could be a valuable marker to track disease progression.
authors.affiliation: Neurodegenerative Disorders, Garvan Institute of Medical Research, Neuroscience Department, Sydney, Australia.
authors.forename: Amanda L
authors.initials: AL
authors.lastname: Wright
authors.forename: Raphael
authors.initials: R
authors.lastname: Zinn
authors.forename: Barbara
authors.initials: B
authors.lastname: Hohensinn
authors.forename: Lyndsey M
authors.initials: LM
authors.lastname: Konen
authors.forename: Sarah B
authors.initials: SB
authors.lastname: Beynon
authors.forename: Richard P
authors.initials: RP
authors.lastname: Tan
authors.forename: Ian A
authors.initials: IA
authors.lastname: Clark
authors.forename: Andrea
authors.initials: A
authors.lastname: Abdipranoto
authors.forename: Bryce
authors.initials: B
authors.lastname: Vissel
mesh_terms: D000367:Age Factors; D000544:Alzheimer Disease / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D016564:Amyloid beta-Protein Precursor / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D056547:CA1 Region, Hippocampal / Q000378:metabolism / Q000473:pathology*; D056654:CA3 Region, Hippocampal / Q000166:cytology / Q000378:metabolism; D002452:Cell Count; D004195:Disease Models, Animal; D042241:Early Diagnosis; D015870:Gene Expression; D005911:Gliosis / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007249:Inflammation; D008297:Male; D008569:Memory Disorders / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008822:Mice, Transgenic; D017628:Microglia / Q000378:metabolism / Q000473:pathology*; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D058225:Plaque, Amyloid / Q000175:diagnosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D013238:Stereotaxic Techniques
chemical_list: D016564:Amyloid beta-Protein Precursor; D015415:Biomarkers
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