Conversion of Synthetic A beta to In Vivo Active Seeds and Amyloid Plaque Formation in a Hippocampal Slice Culture Model

• The aggregation of amyloid-beta peptide (A beta) inbrain is an early event and hallmark of Alzheimers disease (AD). We combined the advantages of in vitro and in vivo approaches to study cerebral beta-amyloidosis by establishing a long-term hippocampal slice culture(HSC) model. While no A beta deposition was noted in untreated HSCs of postnatal A beta precursor protein transgenic (APP tg) mice, A beta deposition emerged in HSCs when cultures were treated once with brain extract from aged APP tg mice and the culture medium was continuously supplemented with synthetic A beta. Seeded A beta deposition was also observed under the same conditions in HSCs derived from wild-type or App-null mice but in no comparable way when HSCs were fixed before cultivation. Both the nature of the brain extract and the synthetic A beta species determined the conformational characteristics of HSCA beta deposition. HSCA beta deposits induced a microglia response, spine loss, and neuritic dystrophy but no obvious neuron loss. Remarkably, in contrast to in vitro aggregated synthetic A beta, homogenates of A beta deposits containing HSCs induced cerebral beta-amyloidosis upon intracerebral inoculation into young APP tg mice. Our results demonstrate that a living cellular environment promotes the seeded conversion of synthetic A beta into a potent in vivo seeding-active form.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Neurovetenskaper (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Neurosciences (hsv//eng)

Nyckelord

alzheimer; amyloid; neurodegeneration; prion-like seeding; slice culture

Publikations- och innehållstyp

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