Kinesin light chain-1 serine-460 phosphorylation is altered in Alzheimer’s disease and regulates axonal transport and processing of the amyloid precursor protein

Mórotz, Gábor M.; Glennon, Elizabeth; Greig, Jenny; Lau, Dawn H. W.; Bhembre, Nishita; Mattedi, Francesca; Muschalik, Nadine; Noble, Wendy; Vagnoni, Alessio; Miller, Christopher C.J.

doi:10.1186/s40478-019-0857-5

Cited by 33 publications

(41 citation statements)

References 63 publications

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“…According to the recently proposed traffic jam theory [34], aging attenuates dynein dysfunction reproduces age-dependent endocytic disturbances, resulting in the intracellular accumulation of A␤PP and its ␤-cleavage products in neurons in cynomolgus monkeys. Another study reported that kinesin phosphorylation is involved in A␤PP processing [35]. In 4-month-old 3×Tg-AD mice, most of Vmes neurons possessed strong A␤ 42 -IR vesicles: however, we did not observe any abnormal behavior at this age, which suggests that the accumulation of A␤ 42 -IR granules in neurons itself is not a trigger for the progression of AD.…”

Section: Discussioncontrasting

confidence: 65%

Neurodegeneration of Trigeminal Mesencephalic Neurons by the Tooth Loss Triggers the Progression of Alzheimer’s Disease in 3×Tg-AD Model Mice

Goto

Kuramoto

Dhar

et al. 2020

JAD

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Background: The mesencephalic trigeminal nucleus (Vmes) is not only anatomically adjacent to the locus coeruleus (LC) but is also tightly associated with the function of the LC. The LC can be the first area in which Alzheimer's disease (AD) develops, although it is unclear how LC neuronal loss occurs. Objective: We investigated whether neuronal death in the Vmes can be spread to adjacent LC in female triple transgenic (3×Tg)-AD mice, how amyloid-␤ (A␤) is involved in LC neuronal loss, and how this neurodegeneration affects cognitive function. Methods: The molars of 3×Tg-AD mice were extracted, and the mice were reared for one week to 4 months. Immunohistochemical analysis, and spatial learning/memory assessment using the Barnes maze were carried out.

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Section: Discussioncontrasting

confidence: 65%

Neurodegeneration of Trigeminal Mesencephalic Neurons by the Tooth Loss Triggers the Progression of Alzheimer’s Disease in 3×Tg-AD Model Mice

Goto

Kuramoto

Dhar

et al. 2020

JAD

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“…KIF5C levels were also reported to be reduced in familial, but not sporadic, AD [ 44 ]. Somewhat more consistent findings have been reported for changes in KLC1 in AD, with decreased protein levels [ 45 – 47 ] speculated to contribute to reduced anterograde axonal transport; nevertheless, others found no change in KLC1 [ 48 ]. In summary, existing observations with respect to AD are inconsistent, thus preventing a conclusion with respect to whether or not changes in KIF5 family members and KLC1 could contribute to changes in anterograde transport.…”

Section: Introductionsupporting

confidence: 69%

“…KLC1 is essential for anterograde transport of many cargoes and was reported to be downregulated in some, but not all, studies of AD [ 45 – 48 ]. To further explore possible shared molecular changes in AD and AD-DS, we measured KLC1 levels.…”

Section: Resultsmentioning

confidence: 99%

Normal levels of KIF5 but reduced KLC1 levels in both Alzheimer disease and Alzheimer disease in Down syndrome: evidence suggesting defects in anterograde transport

et al. 2021

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Background Impaired axonal transport may contribute to the pathogenesis of neurodegenerative diseases, including Alzheimer’s disease (AD) and Down syndrome (DS). Axonal transport is a complex process in which specific motor proteins move cargoes to and from neuronal cell bodies and their processes. Inconsistent reports point to the changes in AD in the levels of the classical anterograde motor protein kinesin family member 5 (KIF5) and the primary neuronal KIF regulator kinesin light chain 1 (KLC1), raising the possibility that anterograde transport is compromised in AD. Methods and materials To address inconsistencies and determine if the shared pathologies in AD and elderly DS subjects with dementia (AD in DS; AD-DS) extend to the changes in KIF5 and KLC1, we measured the levels of all the three KIF5 family members and KLC1 in the AD and AD-DS frontal cortex and AD temporal cortex and cerebellum in samples taken with a short postmortem interval. To support future studies to explore the cell biological basis for any changes detected, we also examined the levels of these proteins in the brains of young and aged adult mice in the Dp (16)1Yey/+ (Dp16) mouse model of DS and J20 mouse model of AD. Results There were no changes in comparison with controls in KIF5 family members in either the AD or AD-DS samples when normalized to either β-actin or glyceraldehyde-3-phosphate dehydrogenase (GAPDH). Interestingly, however, samples from control brains as well as from AD and AD-DS demonstrated strong positive correlations between the levels of KIF5 family members, suggesting positive co-regulated expression. Importantly, while earlier reports pointed to a negative correlation between the levels of the amyloid precursor protein (APP) and KIF5A levels, we found the opposite to be true in AD-DS; this was especially striking given triplication of the APP gene, with increased APP protein levels. AD and control samples showed positive correlations between fl-hAPP and KIF5 members, but they were less consistent. In contrast to the findings for KIF5, the levels of KLC1 were downregulated in the frontal cortex of both AD and AD-DS brains; interestingly, this change was not seen in the AD temporal cortex or cerebellum. As postmortem interval has a negative effect on the levels of KLC1, but not KIF5 members, we analyzed a subset of samples with a very short postmortem interval (PMI) (≤ 6 h), a PMI that was not significantly correlated with the levels of KLC1 in either AD or AD-DS samples; we confirmed the presence of a statistically significant reduction of KLC1 in AD and AD-DS brains as compared with control brains. Studies comparing Dp16 to its euploid control recapitulated human studies in demonstrating no change in KIF5 levels and a positive correlation between the levels of KIF5 family members. J20 mice also showed normal KIF5 levels. However, unlike the AD and AD-DS frontal cortex, KLC1 levels were not reduced in the brains of Dp16 or J20 mice. Conclusion These data point to significant reductions in KLC1 in AD and AD-DS. In so doing, they raise the possibility of compromised KLC1-mediated axonal transport in these conditions, a posit that can now be pursued in model systems in which KLC1 expression is reduced.

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“…Proteins associated with the mechanisms of AD pathology from nuclear factors associated with transcription, and exon processing, proteins associated with transport or secretion and signalling proteins associated with regulating cell survival and cell cycle as well as protein associated with the innate immune response and the cell-death, i.e. apoptotic, necrotic, necroptic and/or phagocytic, pathways were observed with Alzheimer's dementia [84].…”

Section: Discussionmentioning

confidence: 99%

The Plasma Peptides of Alzheimer’s Disease

Florentinus-Mefailoski

Bowden

Scheltens

et al. 2021

Preprint

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BackgroundA practical strategy to discover proteins specific to Alzheimer’s dementia (AD) may be to compare the plasma peptides and proteins from patients with dementia to normal controls and patients with neurological conditions like multiple sclerosis or other diseases. The aim was a proof of principle for a method to discover proteins and/or peptides of plasma that show greater observation frequency and/or precursor intensity in AD. The endogenous tryptic peptides of Alzheimer’s were compared to normals, multiple sclerosis, ovarian cancer, breast cancer, female normal, sepsis, ICU Control, heart attack, along with their institution-matched controls, and normal samples collected directly onto ice.MethodsEndogenous tryptic peptides were extracted from blinded, individual AD and control EDTA plasma samples in a step gradient of acetonitrile for random and independent sampling by LC-ESI-MS/MS with a set of robust and sensitive linear quadrupole ion traps. The MS/MS spectra were fit to fully tryptic peptides within proteins identified using the X!TANDEM algorithm. Observation frequency of the identified proteins was counted using SEQUEST algorithm. The proteins with apparently increased observation frequency in AD versus AD Control were revealed graphically and subsequently tested by Chi Square analysis. The proteins specific to AD plasma by Chi Square with FDR correction were analyzed by the STRING algorithm. The average protein or peptide log10 precursor intensity was compared across disease and control treatments by ANOVA in the R statistical system. ResultsPeptides and/or phosphopeptides of common plasma proteins such as complement C2, C7, and C1QBP among others showed increased observation frequency by Chi Square and/or precursor intensity in AD. Cellular gene symbols with large Chi Square values (χ2 ≥ 25, p ≤ 0.001) from tryptic peptides included KIF12, DISC1, OR8B12, ZC3H12A, TNF, TBC1D8B, GALNT3, EME2, CD1B, BAG1, CPSF2, MMP15, DNAJC2, PHACTR4, OR8B3, GCK, EXOSC7, HMGA1 and NT5C3A among others. Similarly, increased frequency of tryptic phosphopeptides were observed from MOK, SMIM19, NXNL1, SLC24A2, Nbla10317, AHRR, C10orf90, MAEA, SRSF8, TBATA, TNIK, UBE2G1, PDE4C, PCGF2, KIR3DP1, TJP2, CPNE8, and NGF amongst others. STRING analysis showed an increase in cytoplasmic proteins and proteins associated with alternate splicing, exocytosis of luminal proteins, and proteins involved in the regulation of the cell cycle, mitochondrial functions or metabolism and apoptosis. Increases in mean precursor intensity of peptides from common plasma proteins such as DISC1, EXOSC5, UBE2G1, SMIM19, NXNL1, PANO, EIF4G1, KIR3DP1, MED25, MGRN1, OR8B3, MGC24039, POLR1A, SYTL4, RNF111, IREB2, ANKMY2, SGKL, SLC25A5, CHMP3 among others were associated with AD. Tryptic peptides from the highly conserved C-terminus of DISC1 within the sequence MPGGGPQGAPAAAGGGGVSHRAGSRDCLPPAACFR and ARQCGLDSR showed a higher frequency and highest intensity in AD compared to all other disease and controls. ConclusionProteins apparently from the brain that were directly related to Alzheimer’s including Nerve Growth Factor (NFG), Sphingomyelin Phosphodiesterase, Disrupted in Schizophrenia 1 (DISC1), the cell death regulator retinitis pigmentosa (NXNl1) that governs the loss of nerve cells in the retina and the cell death regulator ZC3H12A showed much higher observation frequency in AD plasma. There was a striking agreement between the proteins known to be mutated or dis-regulated in the brains of AD patients with the proteins observed in the plasma of AD patients from endogenous peptides including NBN, BAG1, NOX1, PDCD5, SGK3, UBE2G1, SMPD3 neuronal proteins associated with synapse function such as KSYTL4, VTI1B and brain specific proteins such as TBATA.

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Kinesin light chain-1 serine-460 phosphorylation is altered in Alzheimer’s disease and regulates axonal transport and processing of the amyloid precursor protein

Cited by 33 publications

References 63 publications

Neurodegeneration of Trigeminal Mesencephalic Neurons by the Tooth Loss Triggers the Progression of Alzheimer’s Disease in 3×Tg-AD Model Mice

Neurodegeneration of Trigeminal Mesencephalic Neurons by the Tooth Loss Triggers the Progression of Alzheimer’s Disease in 3×Tg-AD Model Mice

Normal levels of KIF5 but reduced KLC1 levels in both Alzheimer disease and Alzheimer disease in Down syndrome: evidence suggesting defects in anterograde transport

The Plasma Peptides of Alzheimer’s Disease

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