Abstract
Pathologic, biochemical and genetic evidence indicates that accumulation and aggregation of amyloid β-proteins (Aβ) is a critical factor in the pathogenesis of Alzheimer’s disease (AD). Several therapeutic interventions attempting to lower Aβ have failed to ameliorate cognitive decline in patients with clinical AD significantly, but most such approaches target only one or two facets of Aβ production/clearance/toxicity and do not consider the heterogeneity of human Aβ 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 Aβ species. Here we confirmed prior findings that soluble Aβ oligomers, much more than fibrillar amyloid plaque cores or Aβ 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 Aβ levels detected by standard ELISAs. Bioactive AD brain extracts also induce neurotoxicity in iPSC-derived human neurons. Shorter forms of Aβ (including Aβ1–37, Aβ1–38, Aβ1–39), pre-Aβ APP fragments (− 30 to − 1) and N-terminally extended Aβs (− 30 to + 40) each showed much less synaptotoxicity than longer Aβs (Aβ1–42 - Aβ1–46). We found that antibodies which target the N-terminus, not the C-terminus, efficiently rescued Aβ oligomer-impaired LTP and oligomer-facilitated LTD. Our data suggest that preventing soluble Aβ oligomer formation and targeting their N-terminal residues with antibodies could be an attractive combined therapeutic approach.
Highlights
Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive and irreversible cognitive decline
Soluble AD brain extracts rich in aqueously-soluble amyloid β-proteins (Aβ) inhibit hippocampal long-term potentiation (LTP) We previously reported that soluble, human brain-derived Aβ oligomers inhibit hippocampal LTP [35, 64]
We first confirmed that some soluble Aβ-rich extracts of neuropathologically validated human (AD) cerebral cortex robustly and consistently inhibit hippocampal LTP while not altering basal synaptic transmission before the high-frequency stimulus (HFS) (Fig. 1a)
Summary
Alzheimer’s disease (AD) is a neurodegenerative disorder characterized by progressive and irreversible cognitive decline. The pathological hallmarks of AD are the aberrant deposition of extracellular senile plaques comprised of amyloid-beta (Aβ) peptides and intracellular neurofibrillary tangles composed of altered forms of the tau protein. Transgenic APP mutant mouse models showed that increasing β- or γ-secretase activity promotes the production of pathogenic Aβ and induces AD-like pathology, while decreasing their activities by inhibitors can reduce brain Aβ levels and ameliorate AD neuropathology and resultant behavioral deficits [9, 13]. The deposition of Aβ can be accelerated in the brains of APP-transgenic mice after intracerebral or intraperitoneal injection with Aβ aggregate-containing brain homogenate.
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