Abstract
Alzheimer’s disease (AD) is a neurodegenerative pathology associated with aging characterized by the presence of senile plaques and neurofibrillary tangles that finally result in synaptic and neuronal loss. The major component of senile plaques is an amyloid-β protein (Aβ). Recently, we characterized the effects of a single intracerebroventricular (icv) injection of Aβ fragment (25–35) oligomers (oAβ25–35) for up to 3 weeks in rats and established a clear parallel with numerous relevant signs of AD. To clarify the long-term effects of oAβ25–35 and its potential role in the pathogenesis of AD, we determined its physiological, behavioral, biochemical and morphological impacts 6 weeks after injection in rats. oAβ25–35 was still present in the brain after 6 weeks. oAβ25–35 injection did not affect general activity and temperature rhythms after 6 weeks, but decreased body weight, induced short- and long-term memory impairments, increased corticosterone plasma levels, brain oxidative (lipid peroxidation), mitochondrial (caspase-9 levels) and reticulum stress (caspase-12 levels), astroglial and microglial activation. It provoked cholinergic neuron loss and decreased brain-derived neurotrophic factor levels. It induced cell loss in the hippocampic CA subdivisions and decreased hippocampic neurogenesis. Moreover, oAβ25–35 injection resulted in increased APP expression, Aβ1–42 generation, and increased Tau phosphorylation. In conclusion, this in vivo study evidenced that the soluble oligomeric forms of short fragments of Aβ, endogenously identified in AD patient brains, not only provoked long-lasting pathological alterations comparable to the human disease, but may also directly contribute to the progressive increase in amyloid load and Tau pathology, involved in the AD physiopathology.
Highlights
Alzheimer’s disease (AD) is the most common cause of dementia in the elderly and is characterized by a progressive impairment in cognitive functions, resulting from synapse and nerve cell destruction in the brain
Senile plaques are composed of insoluble extracellular aggregates consisting mainly of amyloid-b (Ab) peptides, which are generated by enzymatic cleavages of the amyloid precursor protein (APP), while neurofibrillary tangles (NFT) are the result of hyper- and abnormal phosphorylation of the microtubule-stabilizing protein Tau [1,2]
OAb25–35-HLF was again found at the injection site level where it was trapped by local cells (Fig. 1A)
Summary
Alzheimer’s disease (AD) is the most common cause of dementia in the elderly and is characterized by a progressive impairment in cognitive functions, resulting from synapse and nerve cell destruction in the brain. The histopathological hallmarks of AD include the presence of extracellular senile plaques, intracellular neurofibrillary tangles (NFT), reduction and dysfunction of synapses, neuronal death and reduction in overall brain volume. A correlation between the total amount of Ab in human brain and cognitive decline indicates that the amount of Ab, but not necessarily plaque formation, is important for AD progression [3,4]. Transgenic APP mice demonstrate cognitive decline before plaque formation [5], and soluble oligomers can inhibit cognitive function [6] and long-term potentiation [7,8]. Ab deposits may not even carry the most aggressive toxicity, but instead represent a reserve of toxicity from where toxic oligomeric fragments could be released [9,10,11]
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