Phospho-eIF2α Level Is Important for Determining Abilities of BACE1 Reduction to Rescue Cholinergic Neurodegeneration and Memory Defects in 5XFAD Mice

In the paper

“At 6 months of age, the 5XFAD-associated increase in phospho-eIF2α level was marginal and it was completely abolished in BACE1+/−·5XFAD mice (F (2,11) = 25.76, p<0.05)”

In the paper

“Post-hoc Fisher's PLSD test revealed no significant difference in alternation performances between 5XFAD and BACE1+/−·5XFAD mice (p = 0.24), indicating that BACE1+/− deletion failed to improve the spatial working memory defect in 5XFAD mice at this advanced age.”

In the paper

“the number of ChAT-immunoreactive neurons in 5XFAD and BACE1+/−·5XFAD mice at 15–18 months of age was significantly lower than that of wild-type control mice (F (2,13) = 8.49, p<0.05) and was indistinguishable from each other according to post-hoc Fisher's PLSD test (p = 0.32).”

In the paper

“BACE1+/− deletion significantly suppressed the β-cleavage of APP in 5XFAD mice at 6 months of age resulting in reduced levels of C99 and Aβ42 (by ∼53% and ∼67%, respectively)”

In the paper

“Importantly, we found that BACE1+/− deletion restored the cholinergic defects to normal consistent with improvements in hippocampal spatial memory function in 5XFAD mice at 6 months of age.”

In the paper

“Although heterozygous knockout also reduced BACE1 expression by ∼50% in 15–18-month-old 5XFAD mice in concordance with the reduction in gene copy number, their C99 levels were not significantly lower than age-matched 5XFAD levels.”

In the paper

“5XFAD mice begin to develop visible amyloid deposition as early as 2 months of age and exhibit memory declines on hippocampus-dependent tasks between 4–6 months with moderate Aβ accumulation [8], [28], [29], [30], [31].”

What the sources say

• Not checked yetcites [8] Ohno M Chang L Tseng W Oakley H Citron M 2006 Temporal memory deficits in Alzheimer's mouse models: rescue by genetic deletion of BACE1. Eur J Neurosci 23 251 260 16420434
• Not checked yetcites [28] Oakley H Cole SL Logan S Maus E Shao P 2006 Intraneuronal β-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer's disease mutations: potential factors in amyloid plaque formation. J Neurosci 26 10129 10140 17021169 PMC6674618
• Not checked yetcites [29] Kimura R Ohno M 2009 Impairments in remote memory stabilization precede hippocampal synaptic and cognitive failures in 5XFAD Alzheimer mouse model. Neurobiol Dis 33 229 235 19026746 PMC2741400

In the paper

“the β-secretase (BACE1: β-site amyloid precursor protein cleaving enzyme 1), which is responsible for initiating the production of Aβ, represents an excellent therapeutic target for the treatment of AD [3], [4], [5], [6].”

What the sources say

• Not checked yetcites [3] Citron M 2004 β-Secretase inhibition for the treatment of Alzheimer's disease–promise and challenge. Trends Pharmacol Sci 25 92 97 15102495
• Not checked yetcites [4] Ohno M 2006 Genetic and pharmacological basis for therapeutic inhibition of β- and γ-secretases in mouse models of Alzheimer's memory deficits. Rev Neurosci 17 429 454 17139843
• Not checked yetcites [5] Ohno M 2008 β-Secretase as a prime therapeutic target for Alzheimer's disease: a perspective from mouse model studies. Araki W Recent Advances in the Biology of Secretases, Key Proteases in Alzheimer's Disease Kerala Research Signpost 1 25

In the paper

“partial reduction of BACE1 suffices to attenuate Aβ-related pathology and rescue synaptic and memory deficits in mouse models of AD [18], [19], [20], [21], [22].”

What the sources say

• Not checked yetcites [18] Singer O Marr RA Rockenstein E Crews L Coufal NG 2005 Targeting BACE1 with siRNAs ameliorates Alzheimer disease neuropathology in a transgenic model. Nat Neurosci 8 1343 1349 16136043
• Not checked yetcites [19] Chang WP Downs D Huang XP Da H Fung KM 2007 Amyloid-β reduction by memapsin 2 (β-secretase) immunization. FASEB J 21 3184 3196 17494994
• Not checked yetcites [20] McConlogue L Buttini M Anderson JP Brigham EF Chen KS 2007 Partial reduction of BACE1 has dramatic effects on Alzheimer plaque and synaptic pathology in APP transgenic mice. J Biol Chem 282 26326 26334 17616527

In the paper

“evidence is accumulating that BACE1 expression and activity levels are significantly elevated in sporadic AD brains, which is considered a crucial contributing factor in the pathogenesis of this enigmatic disease [23], [24], [25], [26], [27].”

What the sources say

• Not checked yetcites [23] Fukumoto H Cheung BS Hyman BT Irizarry MC 2002 β-Secretase protein and activity are increased in the neocortex in Alzheimer disease. Arch Neurol 59 1381 1389 12223024
• Not checked yetcites [24] Li R Lindholm K Yang LB Yue X Citron M 2004 Amyloid β peptide load is correlated with increased β-secretase activity in sporadic Alzheimer's disease patients. Proc Natl Acad Sci USA 101 3632 3637 14978286 PMC373514
• Not checked yetcites [25] Yang LB Lindholm K Yan R Citron M Xia W 2003 Elevated β-secretase expression and enzymatic activity detected in sporadic Alzheimer disease. Nat Med 9 3 4 12514700

In the paper

“previous studies also showed that the effects of BACE1+/− deletion in reducing total Aβ levels and plaque load in PDAPP transgenic mice become smaller during the course of disease progression [20]”

What the sources say

• Not checked yetcites [20] McConlogue L Buttini M Anderson JP Brigham EF Chen KS 2007 Partial reduction of BACE1 has dramatic effects on Alzheimer plaque and synaptic pathology in APP transgenic mice. J Biol Chem 282 26326 26334 17616527

In the paper

“complete deletion of BACE1 (BACE1−/−), which abrogates Aβ production, can still rescue impaired spontaneous alternation performance concomitant with the prevention of Aβ deposition and neuronal loss in 5XFAD mice at this advanced age [9].”

What the sources say

• Not checked yetcites [9] Ohno M Cole SL Yasvoina M Zhao J Citron M 2007 BACE1 gene deletion prevents neuron loss and memory deficits in 5XFAD APP/PS1 transgenic mice. Neurobiol Dis 26 134 145 17258906 PMC1876698

In the paper

“spontaneous alternation in the Y-maze that represents a measure of spatial working memory [34]”

What the sources say

• Not checked yetcites [34] Lalonde R 2002 The neurobiological basis of spontaneous alternation. Neurosci Biobehav Rev 26 91 104 11835987

In the paper

“recent studies suggest that phosphorylation of the eukaryotic translation initiation factor-2α (eIF2α) plays an important role in mediating the post-transcriptional upregulation of BACE1 in human AD and 5XFAD mouse brains [32], [33].”

What the sources say

• Not checked yetcites [32] Chang RC Wong AK Ng HK Hugon J 2002 Phosphorylation of eukaryotic initiation factor-2α (eIF2α) is associated with neuronal degeneration in Alzheimer's disease. Neuroreport 13 2429 2432 12499843
• Not checked yetcites [33] O'Connor T Sadleir KR Maus E Velliquette RA Zhao J 2008 Phosphorylation of the translation initiation factor eIF2α increases BACE1 levels and promotes amyloidogenesis. Neuron 60 988 1009 19109907 PMC2667382

In the paper

“Together, our results indicate that partial reduction of BACE1 is not sufficient to block the phospho-eIF2α-dependent BACE1 elevation during the progression of AD, thus limiting its abilities to reduce cerebral Aβ/C99 levels and rescue memory deficits and cholinergic neurodegeneration.”

In the paper

“genetic deletion of BACE1 prevents AD-like pathologies and improves cognitive impairments in different transgenic mouse models [7], [8], [9], [10].”

What the sources say

• Not checked yetcites [7] Ohno M Sametsky EA Younkin LH Oakley H Younkin SG 2004 BACE1 deficiency rescues memory deficits and cholinergic dysfunction in a mouse model of Alzheimer's disease. Neuron 41 27 33 14715132
• Not checked yetcites [8] Ohno M Chang L Tseng W Oakley H Citron M 2006 Temporal memory deficits in Alzheimer's mouse models: rescue by genetic deletion of BACE1. Eur J Neurosci 23 251 260 16420434
• Not checked yetcites [9] Ohno M Cole SL Yasvoina M Zhao J Citron M 2007 BACE1 gene deletion prevents neuron loss and memory deficits in 5XFAD APP/PS1 transgenic mice. Neurobiol Dis 26 134 145 17258906 PMC1876698

In the paper

“the β-secretase (BACE1: β-site amyloid precursor protein cleaving enzyme 1), which is responsible for initiating the production of Aβ, represents an excellent therapeutic target for the treatment of AD [3], [4], [5], [6].”

What the sources say

• Not checked yetcites [3] Citron M 2004 β-Secretase inhibition for the treatment of Alzheimer's disease–promise and challenge. Trends Pharmacol Sci 25 92 97 15102495
• Not checked yetcites [4] Ohno M 2006 Genetic and pharmacological basis for therapeutic inhibition of β- and γ-secretases in mouse models of Alzheimer's memory deficits. Rev Neurosci 17 429 454 17139843
• Not checked yetcites [5] Ohno M 2008 β-Secretase as a prime therapeutic target for Alzheimer's disease: a perspective from mouse model studies. Araki W Recent Advances in the Biology of Secretases, Key Proteases in Alzheimer's Disease Kerala Research Signpost 1 25

In the paper

“The septohippocampal cholinergic pathway has an established role in mediating spatial working memory including spontaneous alternation performance in the Y-maze [35], [36], [37].”

What the sources say

• Not checked yetcites [35] Ohno M Yamamoto T Watanabe S 1992 Effects of intrahippocampal injections of N-methyl-D-aspartate receptor antagonists and scopolamine on working and reference memory assessed in rats by a three-panel runway task. J Pharmacol Exp Ther 263 943 950 1361577
• Not checked yetcites [36] Feasey-Truger KJ Li BH ten Bruggencate G 1992 Lesions of the medial septum which produce deficits in working/spatial memory do not impair long-term potentiation in the CA3 region of the rat hippocampus in vivo. Brain Res 591 296 304 1446243
• Not checked yetcites [37] Chang Q Gold PE 2004 Impaired and spared cholinergic functions in the hippocampus after lesions of the medial septum/vertical limb of the diagonal band with 192 IgG-saporin. Hippocampus 14 170 179 15098723

In the paper

“At ≥9 months of age, 5XFAD mice show severe memory deficits together with further developed Aβ pathology and marked synaptic degeneration and neuronal loss [9], [21], [28], [30], [31].”

What the sources say

• Not checked yetcites [9] Ohno M Cole SL Yasvoina M Zhao J Citron M 2007 BACE1 gene deletion prevents neuron loss and memory deficits in 5XFAD APP/PS1 transgenic mice. Neurobiol Dis 26 134 145 17258906 PMC1876698
• Not checked yetcites [21] Devi L Ohno M 2010 Genetic reductions of β-site amyloid precursor protein-cleaving enzyme 1 and amyloid-β ameliorate impairment of conditioned taste aversion memory in 5XFAD Alzheimer's disease model mice. Eur J Neurosci 31 110 118 20092558 PMC2887274
• Not checked yetcites [28] Oakley H Cole SL Logan S Maus E Shao P 2006 Intraneuronal β-amyloid aggregates, neurodegeneration, and neuron loss in transgenic mice with five familial Alzheimer's disease mutations: potential factors in amyloid plaque formation. J Neurosci 26 10129 10140 17021169 PMC6674618

In the paper

“However, these phenotypes are not observed in BACE1+/− knockout mice, suggesting that potential mechanism-based side effects might occur only in completely abolishing BACE1 activity but not in partially inhibiting it.”

In the paper

“In line with the discovery of various BACE1 physiological substrates besides APP such as neuregulins and β-subunits of the voltage-gated sodium channel, recent studies reveal some liabilities of complete BACE1 deletion including hypomyelination and altered synaptic functions or neuronal activities [4], [5], [6].”

What the sources say

• Not checked yetcites [4] Ohno M 2006 Genetic and pharmacological basis for therapeutic inhibition of β- and γ-secretases in mouse models of Alzheimer's memory deficits. Rev Neurosci 17 429 454 17139843
• Not checked yetcites [5] Ohno M 2008 β-Secretase as a prime therapeutic target for Alzheimer's disease: a perspective from mouse model studies. Araki W Recent Advances in the Biology of Secretases, Key Proteases in Alzheimer's Disease Kerala Research Signpost 1 25
• Not checked yetcites [6] Cole SL Vassar R 2007 The Alzheimer's disease β-secretase enzyme, BACE1. Mol Neurodegener 2 22 18005427 PMC2211305

In the paper

“accumulation of the amyloid-β (Aβ) peptide plays a central role in triggering a pathogenic cascade ultimately leading to neuronal death and profound memory deficits [1], [2].”

What the sources say

• Not checked yetcites [1] Hardy JA Higgins GA 1992 Alzheimer's disease: the amyloid cascade hypothesis. Science 256 184 185 1566067
• Not checked yetcites [2] Hardy J Selkoe DJ 2002 The amyloid hypothesis of Alzheimer's disease: progress and problems on the road to therapeutics. Science 297 353 356 12130773

In the paper

“but also indicate that neurotoxic Aβ42 and/or C99 species are responsible for killing cholinergic neurons.”

In the paper

“Notably, phosphorylation of eIF2α, which increases age-dependently and induces BACE1 elevation in the 5XFAD model, seems to be important for determining the abilities of partial BACE1 reduction to improve cholinergic and mnemonic deficits.”

In the paper

“Interestingly, transgenic overexpression or central administration of the potentially amyloidogenic C99 fragments has been reported to induce memory defects and neurodegeneration [45], [46], [47], [48], [49].”

What the sources say

• Not checked yetcites [45] Lee KW Im JY Song JS Lee SH Lee HJ 2006 Progressive neuronal loss and behavioral impairments of transgenic C57BL/6 inbred mice expressing the carboxy terminus of amyloid precursor protein. Neurobiol Dis 22 10 24 16289866
• Not checked yetcites [46] Nalbantoglu J Tirado-Santiago G Lahsaini A Poirier J Goncalves O 1997 Impaired learning and LTP in mice expressing the carboxy terminus of the Alzheimer amyloid precursor protein. Nature 387 500 505 9168112
• Not checked yetcites [47] Berger-Sweeney J McPhie DL Arters JA Greenan J Oster-Granite ML 1999 Impairments in learning and memory accompanied by neurodegeneration in mice transgenic for the carboxyl-terminus of the amyloid precursor protein. Brain Res Mol Brain Res 66 150 162 10095087

In the paper

“All experiments were done blind with respect to the genotype of the mice at 6 and 15–18 months of age, and were conducted with the approval of the Nathan Kline Institute Animal Care and Use Committee (AP2008-268).”

In the paper

“Consistent with the so-called “cholinergic hypothesis” of AD [50], several APP transgenic mouse models reproduce cholinergic neurodegeneration as evidenced by dystrophic neurites, decreased fiber density in the hippocampus and cortex, and reductions in the medial septum and basal forebrain neuron volume/number [51], [52], [53], [54];”

What the sources say

• Not checked yetcites [51] Bellucci A Luccarini I Scali C Prosperi C Giovannini MG 2006 Cholinergic dysfunction, neuronal damage and axonal loss in TgCRND8 mice. Neurobiol Dis 23 260 272 16766197
• Not checked yetcites [52] Christensen DZ Bayer TA Wirths O 2010 Intracellular Aβ triggers neuron loss in the cholinergic system of the APP/PS1KI mouse model of Alzheimer's disease. Neurobiol Aging 31 1153 1163 18771817
• Not checked yetcites [53] Boncristiano S Calhoun ME Kelly PH Pfeifer M Bondolfi L 2002 Cholinergic changes in the APP23 transgenic mouse model of cerebral amyloidosis. J Neurosci 22 3234 3243 11943824 PMC6757538

In the paper

“The failure of BACE1+/− ablation to rescue the septohippocampal degeneration found in 15–18-month-old 5XFAD mice in parallel with no amelioration of memory function supports the view that Aβ/C99-dependent cholinergic dysfunction represents a critical mechanism responsible for memory impairments in 5XFAD mice.”