Chronic Presence of Oligomeric Aβ Differentially Modulates Spine Parameters in the Hippocampus and Cortex of Mice With Low APP Transgene Expression

Abstract

Alzheimer's disease is regarded as a synaptopathy with a long presymptomatic phase. Soluble, oligomeric amyloid-β (Aβ) is thought to play a causative role in this disease, which eventually leads to cognitive decline. However, most animal studies have employed mice expressing high levels of the Aβ precursor protein (APP) transgene to drive pathology. Here, to understand how the principal neurons in different brain regions cope with moderate, chronically present levels of Aβ, we employed transgenic mice expressing equal levels of mouse and human APP carrying a combination of three familial AD (FAD)-linked mutations (Swedish, Dutch, and London), that develop plaques only in old age. We analyzed dendritic spine parameters in hippocampal and cortical brain regions after targeted expression of EGFP to allow high-resolution imaging, followed by algorithm-based evaluation of mice of both sexes from adolescence to old age. We report that Aβ species gradually accumulated throughout the life of APP SDL mice, but not the oligomeric forms, and that the amount of membrane-associated oligomers decreased at the onset of plaque formation. We observed an age-dependent loss of thin spines under most conditions as an indicator of a loss of synaptic plasticity in older mice. We further found that hippocampal pyramidal neurons respond to increased Aβ levels by lowering spine density and shifting spine morphology, which reached significance in the CA1 subfield. In contrast, the spine density in cortical pyramidal neurons of APP SDL mice was unchanged. We also observed an increase in the protein levels of PSD-95 and Arc in the hippocampus and cortex, respectively. Our data demonstrated that increased concentrations of Aβ have diverse effects on dendritic spines in the brain and suggest that hippocampal and cortical neurons have different adaptive and compensatory capacity during their lifetime. Our data also indicated that spine morphology differs between sexes in a region-specific manner.

Caspase-cleaved tau is senescence-associated and induces a toxic gain of function by putting a brake on axonal transport

“…Micrographs (voxel size: 0.06 × 0.06 × 0.30 µm) were blind deconvolved using AutoQuantX vX3.0.5 software (Media Cybernetics Inc., USA) in order to improve the signal-to-noise ratio, and the analysis of individual dendritic spines was carried out using the morphometric software 3DMA v0204 [ 39 ]. The spines were classified into mushroom, stubby and thin based on the ratio of head to neck diameter and the ratio of length to neck diameter as described before [ 40 , 41 ]. Confocal tiles of complete CA1 hippocampal arbors were acquired as previously described [ 42 ] using a Zeiss 510 META NLO confocal laser scanning microscope (Zeiss, Oberkochen, Germany) equipped with a ×40 oil-immersion objective (NA, 1.3) and a Helium/Neon 543 nm laser governed by LSM 510 v4.0 SP2 software.…”

Tau and α-synuclein shape microtubule organization and microtubule-dependent transport in neuronal dendrites

“…To determine whether a negative correlation between tau and α-syn levels also exists under disease conditions, we investigated a possible correlation between the levels of the two proteins in a mouse model of amyloidosis and AD patients. Interestingly, when examining lysates from hemibrains of old mice with chronic amyloidosis (Hrynchak et al, 2020), we observed no decrease in tau protein with age and the negative correlation between tau and α-syn was also absent (Figs. 5A, B).…”

Homomeric and Heteromeric α7 Nicotinic Acetylcholine Receptors in Health and Some Central Nervous System Diseases

“…Indeed, the amyloid peptide Aβ1-42 has been shown to decrease actin dynamics in vitro and reduce the F-actin/G-actin ratio in synaptosomes of APPswe/PS1ΔE9 mice at as early as 1 month of age [ 125 ]. This effect precedes amyloid plaque formation and follows disease progression [ 126 , 127 ]. Aβ oligomers induce the activation of calcineurin, which results in actin depolymerization and subsequent spine dystrophy and eventually loss of actin fibers [ 128 , 129 ].…”

“…Deposition of Aβ in plaques would decrease the availability of soluble forms of Aβ, thus precluding signaling towards actin depolymerization in an attempt to protect spine structure. This mechanism may be exhausted at some point in the evolution of the disease and may explain the reduced levels of F-actin measured in synaptosomes from human postmortem brain tissue in Alzheimer patients with mild cognitive impairment [ 125 , 126 ].…”