Parvalbumin-Positive Neuron Loss and Amyloid-β Deposits in the Frontal Cortex of Alzheimer’s Disease-Related Mice

Abstract

Alzheimer's disease (AD) has several hallmark features including amyloid-β plaque deposits and neuronal loss. Here, we characterized amyloid-β plaque aggregation and parvalbumin-positive (PV) GABAergic neurons in 6 -9 month old 5xFAD mice harboring mutations associated with familial AD. We used immunofluorescent staining to compare three regions in the frontal cortexprelimbic (PrL), cingulate (Cg, including Cg1 and Cg2) and secondary motor (M2) corticesalong with primary somatosensory (S1) cortex. We quantified the density of amyloid-β plaques, which showed significant laminar and regional vulnerability. There were more plaques of larger sizes in deep layers compared to superficial layers. Total plaque burden was higher in frontal regions compared to S1. We also found layer-and region-specific differences across genotype in the density of PV interneurons. PV neuron density was lower in 5xFAD mice than wild-type, particularly in deep layers of frontal regions, with Cg (−50%) and M2 (−39%) exhibiting the largest reduction. Using in vivo two-photon imaging, we longitudinally visualized the loss of frontal cortical PV neurons across four weeks in the AD mouse model. Overall, these results provide information about amyloid-β deposits and PV neuron density in a widely used mouse model for AD, implicating deep layers of frontal cortical regions as being especially vulnerable.

Loss of Hippocampal Calretinin and Parvalbumin Interneurons in the 5XFAD Mouse Model of Alzheimer’s Disease

“…Previous studies analyzed the number of PV-positive GABAergic neurons in different regions of the frontal cortex of the 5XFAD mouse model. PV neuron density was reported to be significantly reduced in particular in deep cortical layers such as cingulate and secondary motor cortices (Ali et al, 2019), confirming data from others demonstrating an $30% reduction of PVpositive cell bodies in cortical Layer IV in 12-monthold 5XFAD mice (Flanigan et al, 2014). The observed significantly reduced number of both CR-and PVpositive cells in the hippocampus of 5XFAD mice is in line with results from other AD transgenic mouse models harboring substantial amyloidosis.…”

Microglia as hackers of the matrix: sculpting synapses and the extracellular space

“…PNN deficits/decreases have also been observed across more diverse diseases, many if not all of which are also generally associated with microglial activation, including multiple sclerosis [169], stroke [180][181][182][183][184], traumatic brain injury [185,186], spinal cord injury [187], epilepsy [188,189], obesogenic high fat and high sugar diet consumption [190], glioma [160], Alzheimer's disease [90,[191][192][193], and schizophrenia [167,[194][195][196]. The loss of protective PNNs leaves PV + and other enwrapped neurons susceptible to injury [92,156,157], and accordingly, we found that PNN reductions preceded decreases in PV + neurons in AD [90], where PV + cells are particularly relevant to disease [197][198][199][200]. Indeed, PNN loss is associated with neuronal death and/or degeneration in a number of disease contexts [160,169,176,180,190,193,201].…”

Microglia facilitate loss of perineuronal nets in the Alzheimer's disease brain

“…Impaired PV+ interneuron functioning has recently been linked to neuronal network hypersynchrony/hyperexcitability and cognitive deficits in AD [ 30 , 31 ], and PV+ cell loss occurs across multiple AD models [59] , [60] , [61] , [62] . Given the protective and physiological benefits PNNs confer upon the neurons they enwrap [ 39 , 63 ], we set out to investigate the temporal pattern of PV+ interneuron loss reported in the 5xFAD brain [ 59 , 64 ] relative to the onset of overt PNN reductions. To accomplish this, we immunolabeled and quantified PV+ cell density at 4, 8, 12, and 18mo in male and female 5xFAD and WT subiculum ( Fig.…”