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

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 As (-30 to +40) each showed much less synaptotoxicity than longer As (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.