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Abstract
The purpose of our study is to investigate early cellular, molecular, morphological and behavioral changes in humanized amyloid-beta-knock-in (hAbKI) mice. Using seven-month-old homozygous hAbKI mice, we studied behavioral phenotype parameters, including spatial learning and memory (Morris Water Maze), locomotor activity (open field), working memory (Y-maze) and motor coordination (rotarod); mRNA abundance, protein levels, soluble amyloid-beta 40 and 42 levels and regional immunoreactivities of key markers of mitochondrial dynamics, mitochondrial biogenesis, synaptic health, mitophagy and autophagy; mitochondrial function and using transmission electron microscopy & Golgi–Cox staining, we assessed mitochondrial morphology and dendritic spines. Our extensive behavioral analysis revealed that seven-month-old hAbKI mice showed impairments in motor coordination, reduced locomotor and exploration activities, impairments in working memory and spatial learning and memory. Our mRNA and protein analyses revealed the increased expression of mitochondrial-fission genes and reduced expression of mitochondrial-fusion, mitochondrial-biogenesis, synaptic, autophagy and mitophagy genes in seven-month-old hAbKI mice. An immunofluorescence analysis revealed altered immunoreactivities and agreed with the immunoblot results. Transmission-electron-microscopy data revealed increased mitochondrial fragmentation and reduced mitochondrial length in both hippocampal and cortical tissues of seven-month-old hAbKI mice and mitochondrial function defective. A Golgi–Cox-staining analysis revealed reduced dendritic spines in both cerebral cortices and hippocampi of hAbKI mice. Soluble amyloid-beta (1–40 and 1–42) were detected in three-month-old hAbKI mice and progressively increased in seven-month-old mice. These observations suggest that the human amyloid-beta peptide is sufficient to cause behavioral, mitochondrial, synaptic and ultrastructural changes in seven-month-old hAbKI mice. Our study findings also suggest that hAbKI mice might serve as a model for preclinical studies of preventive therapies.
Highlights
Alzheimer’s disease (AD) is a progressive, neurodegenerative disorder and is the most common cause of dementia in older people [1,2] Currently, over 50 million people worldwide are living with AD-related dementia, and this number is expected to increase to 152 million by 2050 (Alzheimer Association 2021)
In the current study, using seven-month-old homozygous humanized amyloid-beta-knock-in (hAbKI) mice and agematched WT mice, we studied 1) behavioral-phenotype parameters, including spatial learning and memory (Morris Water Maze), locomotor activity, working memory (Y-maze) and motor coordination; 2) mRNA abundance and protein levels of mitochondrial fission (Drp1 and Fis1), mitochondrial fusion (Mfn1, Mfn2 and Opa1), Cells 2022, 11, 733 mitochondrial biogenesis (PGC1a, Nrf1, Nrf2 and TFAM), synaptic health, mitophagy (PINK1 and PARKIN) and autophagy (ATG5, Beclin, LC3A and LC3B); 3) we assessed cortical and hippocampal immunoreactivities of the above-mentioned proteins; 4) mitochondrial ultrastructural changes using transmission electron microscopy; and 5) dendritic-spine length and number using Golgi–Cox-staining analysis
In the accelerating rotarod test, hAbKI mice exhibited a reduced latency to fall compared to WT mice (p < 0.0071, Figure 1A), indicating that seven-month-old hAbKI mice exhibited motor deficits
Summary
Alzheimer’s disease (AD) is a progressive, neurodegenerative disorder and is the most common cause of dementia in older people [1,2] Currently, over 50 million people worldwide are living with AD-related dementia, and this number is expected to increase to 152 million by 2050 (Alzheimer Association 2021). AD is associated with the loss of synapses [3,4], synaptic dysfunction [5], mitochondrial structural and functional abnormalities [6–8], microRNA deregulation [9,10], inflammatory responses [11], neuronal loss, accumulation of amyloid-beta (Aβ) [12,13] and phosphorylated tau (p-tau) [14–16]. FAD is caused by genetic mutations in amyloid-beta-precursor protein (APP), presenilin (PSEN1), and presenilin 2 (PSEN2), which lead to the overproduction of Aβ plaques [20–23]. The APOE4 genotype is a major risk factor for AD, and the age of disease onset is 65 years and beyond [24]
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