Early Neuronal Loss and Axonal/Presynaptic Damage is Associated with Accelerated Amyloid-β Accumulation in AβPP/PS1 Alzheimer's Disease Mice Subiculum

Abstract

The progressive cognitive decline leading to dementia in Alzheimer's disease (AD) patients is the consequence of a severe loss of synapses and neurons affecting particular cell subpopulations in selected brain areas, with the subiculum being one of the earliest regions displaying severe atrophy and pathology. The lack of significant neuronal loss in most AD models is, in fact, the major shortcoming for the preclinical evaluation of drugs that could have greater potential in patients to alleviate or prevent this disease. In this study, using immunohistochemical and stereological approaches, we have analyzed the histopathological events in the subiculum of AβPP751SwedLondon/PS1M146L mice, a transgenic model that displays neuronal vulnerability at early ages in hippocampus and entorhinal cortex. Our results indicate that the subiculum is the earliest affected region in the hippocampus, showing a selective early loss of both principal neurons (28%) and SOM-positive interneurons (69%). In addition, our data demonstrate the existence of an early axonal and synaptic pathology, which may represent the beginning of the synaptic disruption and loss. These neurodegenerative processes occur in parallel, and closely related, with the onset and accelerated progression of the extracellular amyloid-β deposition, thus suggesting plaques as major contributors of neuronal/axonal damage. Data reported here indicate that this AD model displays a selective AD-like neurodegenerative phenotype in highly vulnerable regions, including the subiculum, and therefore can be a very useful model for testing the therapeutic ability of potential compounds to protect neurons and ameliorate disease symptoms.

Aerosol Delivery of Curcumin Reduced Amyloid-β Deposition and Improved Cognitive Performance in a Transgenic Model of Alzheimer’s Disease

“…Our data are consistent with recent reports, which show the geospatial significance of the subiculum in the early onset of AD [26, 34]. The subiculum serves as the major output structure of the hippocampal formation to widespread subcortical and cortical areas [35].…”

Distinct disease‐sensitive GABAergic neurons in the perirhinal cortex of Alzheimer's mice and patients

“…We have previously reported that SOM‐positive interneuron population was substantially reduced in the hippocampus and the entorhinal cortex of our APP/PS1 transgenic model at early ages . Thus, we now analyzed the vulnerability of this GABAergic interneuron subset in the perirhinal cortex.…”

“…The mechanisms underlying the AD‐associated vulnerability of SOM cells are still unknown, but as we have previously suggested , the extracellular Abeta could be a major factor involved. Thus, as we show in the perirhinal cortex of AD patients and APP/PS1 mice, the loss of SOM neurons is temporally and spatially associated with the amyloid pathology, including the formation of SOM‐positive dystrophies surrounding the Abeta plaques.…”

The proof-of-concept of ASS234: Peripherally administered ASS234 enters the central nervous system and reduces pathology in a male mouse model of Alzheimer disease

“…1 Although it is not clear whether abnormal processing of the amyloid pre cursor protein (APP) is the initial cause or rather a late event in the pathophysiology of Alzheimer disease, 2 the generation of Aβ from its precursor protein APP induces oxidative stress and plays a critical role in the pathogenesis and advancement of the disease, producing neuronal injury and loss, inflamma tion and characteristic activation of microglia and astrocytic cells. [3][4][5][6] Together with aberrant Aβ deposits in the neuropil, a genetic basis is essential in influencing the onset and/or modifying the progression of the disease. 7 Genomic factors…”