Selective Regional Loss of Cortical Synapses Lacking Presynaptic Mitochondria in the 5xFAD Mouse Model

Abstract

Synaptic loss in Alzheimer's disease (AD) is strongly correlated with cognitive impairment. Accumulating evidence indicates that amyloid pathology leads to synaptic degeneration and mitochondrial damage in AD. However, it remains unclear whether synapses and presynaptic mitochondria are differentially affected in various cortical regions of the AD brain at the ultrastructural level. Using serial block-face scanning electron microscopy, we assessed synaptic structures in the medial prefrontal cortex (mPFC) and primary visual cortex (V1) of the 5xFAD mouse model of AD. At 6 months of age, 5xFAD mice exhibited significantly elevated levels of amyloid deposition in layer 2/3 of the mPFC but not V1. Accordingly, three-dimensional reconstruction of synaptic connectivity revealed a significant reduction in excitatory synaptic density in layer 2 of the mPFC, but not V1, of male transgenic mice. Notably, the density of synapses lacking presynaptic mitochondria was selectively decreased in the mPFC of 5xFAD mice, with no change in the density of mitochondria-containing synapses. Further classification of spines into shape categories confirmed a preferential loss of thin spines whose presynaptic boutons were largely devoid of mitochondria in the 5xFAD mPFC. Furthermore, the number of mitochondria per bouton in spared mitochondria-containing boutons was reduced in the mPFC, but not V1, of 5xFAD mice. Collectively, these results highlight region-specific vulnerability of cortical synapses to amyloid deposition and suggest that the presence of presynaptic mitochondria may affect synaptic degeneration in AD.

Damaged mitochondria coincide with presynaptic vesicle loss and abnormalities in alzheimer’s disease brain

“…Our study thus provided strong support of increased presynaptic mitochondrial damage in AD which is consistent with well documented synaptic mitochondrial dysfunction in the brain of AD patients [ 23 , 28 ]. Furthermore, similar synaptic mitochondrial deficits were reported in cell and animal models of AD [ 32 ]: Aβ treatment of synaptosome caused mitochondrial dysfunction [ 36 ] as well as swollen synaptic mitochondria along with significantly reduced number of SVs [ 45 ]; Significantly reduced presynaptic mitochondria [ 63 ] and increase in presynaptic mitochondria lacking cristae and bioenergetics deficits along with reduced SVs were found in 5xFAD mice [ 2 ]. Mitochondria are strategically localized to presynaptic sites to meet the local needs and the proximity of mitochondria influences synaptic vesicle number [ 67 ].…”

“…It was demonstrated that amyloid-β (Aβ) significantly interfered with mitochondrial dynamics and distribution and caused changes in both presynapse and spines in cell models of AD [ 22 , 56 , 77 , 79 – 81 ]. Moreover, synaptic mitochondria showed greater alterations and Aβ accumulation [ 22 ] and there was selective regional loss of cortical synapses lacking presynaptic mitochondria in AD mouse models [ 63 ]. While regional loss of mitochondria in presynaptic terminals has also been reported in cortical regions of AD autopsy brain samples [ 49 ], the use of autopsied brain samples limited detailed analysis on synaptic and mitochondrial changes and their relationship.…”

Downregulation of Sirtuin 1 Does Not Account for the Impaired Long-Term Potentiation in the Prefrontal Cortex of Female APPswe/PS1dE9 Mice Modelling Alzheimer’s Disease

“…Since metabolic deregulation in synapses might also account for the deterioration of synaptic plasticity and memory performance (reviewed e.g., [ 71 ]) and there is compelling evidence that metabolic set up of prefrontocortical synapses is modified in animal models of AD [ 72 ], we explored the possibility that alterations of intracellular metabolic coordinators might account for the deterioration of PFC-LTP observed in female APP/PS1 mice. We focused on sirtuins since their levels are reduced in the hippocampus of AD patients [ 17 , 18 ] and animal models [ 19 , 20 ] and their genetic and pharmacological manipulation has been reported to ameliorate several features of AD in animal models [ 21 , 22 , 23 ].…”

Advances in proteomic phenotyping of microglia in neurodegeneration

“…Uniquely in humans, AD pathology significantly reduces the abundance of specific synaptic proteins (CAMK2 and NPTX2) and neurotrophic factors (BDNF and VGF) [86], a trend which deviates from 5xFAD mouse models in this study. While synaptic loss in 5xFAD mice is well documented; several studies converge to show significant synaptic loss only beyond 4 months of age, none of these studies herein referenced note a decrease in the proteins CAMK2 or NPTX2 specifically [84, 117–121]. Due to the limitations of bulk‐brain proteomics, the microglial‐specific proteomic changes taking place during the transition from MCI to AD in humans or in mouse models of neurodegeneration are currently not known, despite many studies linking complement signaling with synaptic loss and cognitive decline in both mouse and human studies.…”