Decoding the synaptic dysfunction of bioactive human AD brain soluble A? to inspire novel therapeutic avenues for Alzheimer's disease.

ABSTRACT: Pathologic, biochemical and genetic evidence indicates that accumulation and aggregation of amyloid ?-proteins (A?) is a critical factor in the pathogenesis of Alzheimer's disease (AD). Several therapeutic interventions attempting to lower A? have failed to ameliorate cognitive decline in patients with clinical AD significantly, but most such approaches target only one or two facets of A? production/clearance/toxicity and do not consider the heterogeneity of human A? species. As synaptic dysfunction may be among the earliest deficits in AD, we used hippocampal long-term potentiation (LTP) as a sensitive indicator of the early neurotoxic effects of A? species. Here we confirmed prior findings that soluble A? oligomers, much more than fibrillar amyloid plaque cores or A? monomers, disrupt synaptic function. Interestingly, not all (84%) human AD brain extracts are able to inhibit LTP and the degree of LTP impairment by AD brain extracts does not correlate with A? levels detected by standard ELISAs. Bioactive AD brain extracts also induce neurotoxicity in iPSC-derived human neurons. Shorter forms of A? (including A?_1-37, A?_1-38, A?_1-39), pre-A? APP fragments (-?30 to -?1) and N-terminally extended A?s (-?30 to +?40) each showed much less synaptotoxicity than longer A?s (A?_1-42 - A?_1-46). We found that antibodies which target the N-terminus, not the C-terminus, efficiently rescued A? oligomer-impaired LTP and oligomer-facilitated LTD. Our data suggest that preventing soluble A? oligomer formation and targeting their N-terminal residues with antibodies could be an attractive combined therapeutic approach.

SUBMITTER: Li S 

PROVIDER: S-EPMC6225562 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature