Selective serotonin reuptake inhibitor citalopram ameliorates cognitive decline and protects against amyloid beta-induced mitochondrial dynamics, biogenesis, autophagy, mitophagy and synaptic toxicities in a mouse model of Alzheimer’s disease

Abstract

In the current study, we investigated the protective role of citalopram against cognitive decline, impaired mitochondrial dynamics, defective mitochondrial biogenesis, defective autophagy, mitophagy, and synaptic dysfunction in APP transgenic mouse model of Alzheimer’s disease (ad). We treated 12-month-old wild-type (WT) and age-matched transgenic APP mice with citalopram for 2 months. Using Morris Water Maze and rotarod tests, quantitative RT-PCR, immunoblotting, biochemical methods and transmission electron microscopy methods, we assessed cognitive behavior, RNA and protein levels of mitochondrial dynamics, biogenesis, autophagy, mitophagy, synaptic, ad-related and neurogenesis genes in wild-type and APP mice treated and untreated with citalopram. Citalopram-treated APP mice relative to citalopram-untreated APP mice, exhibited improved cognitive behavior. Increased levels of mRNA associated with mitochondrial fission and ad-related genes; decreased levels of fusion, biogenesis, autophagy, mitophagy, synaptic and neurogenesis genes were found in APP mice relative to WT mice. However, APP mice treated with citalopram compared to citalopram-untreated APP mice, revealed reduced levels of the mitochondrial fission and ad-related genes and increased fusion, biogenesis, autophagy, mitophagy, synaptic and neurogenesis genes. Our protein data agrees with the mRNA levels. Transmission electron microscopy revealed significantly increased mitochondrial numbers and reduced mitochondrial length in APP mice; these were reversed in citalopram-treated APP mice. Further, Golgi-cox staining analysis revealed reduced dendritic spines in APP mice relative to WT mice. However, citalopram-treated APP mice showed significantly increased dendritic spines, indicating that citalopram enhances spine density, synaptic activity and improved cognitive function in APP mice. These findings suggest that citalopram reduces cognitive decline, Aβ levels, and mitochondrial and synaptic toxicities and may have a strong protective role against mutant APP and Aβ-induced injuries in patients with depression, anxiety, and ad.

A partial reduction of Drp1 enhances mitophagy, autophagy, mitochondrial biogenesis, dendritic spines and synaptic activity in a transgenic Tau mouse model of Alzheimer disease

“…The long-term goal of our study was to understand molecular mechanisms involved in defective mitophagy in the progression and pathogenesis of AD. Emerging evidence from AD cell cultures, mouse and postmortem studies suggest that mitophagy is defective early on in the progression of disease [6, 39, 40, 7, 8, 26, 41, 18, 22, 29, 20, 24, 23]. Several studies provided compelling evidence that Aβ and P-Tau interacts with a large number of mitochondrial proteins such as Drp1, VDAC1 (voltage-dependent anion channel 1), CypD (cyclophilin D) and ABAD (amyloid beta-induced alcohol dehydrogenase), leading to induced free radical production, increased lipid peroxidation, and depletion of major mitophagy proteins, PINK1 and Parkin [6, 39, 40, 7, 8, 26, 41, 42, 22, 29, 20, 24, 23, 43, 44, 45].…”

“…Our laboratory has been working to understand molecular events in mitochondria, aging, synapse and Aβ & P-Tau in AD over the last 2 decades; we have found that Aβ and P-Tau interacts with mitochondrial fission protein, Drp1, and mitochondrial outer membrane protein VDAC1, these interactions enhance GTPase Drp1 activity, increases mitochondrial fragmentation and most importantly depletes mitophagy proteins PINK1 and Parkin [26, 26, 41, 42, 22, 29, 20, 24, 23]. Based on these observations, we propose that a partial reduction of Drp1 reduces mitochondrial fragmentation, enhances biogenesis, mitophagy/autophagy, synaptic activity, dendritic spines, and improve cognitive functions in AD.…”

“…Further, using AD transgenic mice lines, studies have found increased production of free radicals and lipid peroxidation, and reduced levels of cytochrome c oxidase activity and synaptic ATP in AD-affected brain regions (cortex and hippocampus) [17][18][19], in the primary neurons of AD transgenic mice [15] and neurons expressing mutant APP and Aβ [20][21][22][23][24]. These findings strongly implicate mitochondrial dysfunction and oxidative stress in AD pathogenesis.…”

“…Therefore, any damaged/dysfunctional mitochondrial quality has a significant effect on neuronal health. Recent in vitro (APP hippocampal primary neurons) and in vivo studies (APP, APP/PS1, CRND8, and Tau mice) [26, 18, 19, 15, 27, 28, 22, 23, 20, 24, 29] revealed increased mitochondrial fragmentation, mitochondria dysfunction and defective mitophagy, strongly indicating that Aβ and P-Tau induced defective mitophagy in AD [30, 4]. Studies conducted in different AD models across species have revealed that abnormal mitochondria function, defective mitochondria dynamics, and compromised mitophagy lead to increased oxidative stress, synaptic dysfunction, neuronal loss, and cognitive decline, thereby contributing to enhanced AD pathologies [29, 26, 18, 19, 15].…”

Mitophagy enhancers against phosphorylated Tau-induced mitochondrial and synaptic toxicities in Alzheimer disease

“…Mitochondrial abnormalities, including changes in mitochondrial DNA, mitochondrial gene expressions, mitochondrial ATP, mitochondrial enzymatic activities, mitochondria-induced increased free radicals, mitochondria-induced lipid peroxidation, reduced axonal transport, impaired biogenesis & dynamics and defective mitophagy are extensively reported in progression and pathogenesis of AD [4][5][6][7][8][9][10][11][12][13][14][15][16][17][26][27][28][29][30][31][32][33][34][35][36][37] . These changes are age-dependent, irrespective of type of AD -early-onset familial and late-onset sporadic.…”