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. 2019 Feb;56(2):1366-1390.
doi: 10.1007/s12035-018-1114-9. Epub 2018 Jun 8.

Multifaceted Regulation of ALDH1A1 by Cdk5 in Alzheimer's Disease Pathogenesis

Kumar Nikhil  1 , Keith Viccaro  1 , Kavita Shah  2
Affiliations

Multifaceted Regulation of ALDH1A1 by Cdk5 in Alzheimer's Disease Pathogenesis

Kumar Nikhil et al. Mol Neurobiol. 2019 Feb.

Abstract

This study revealed multifaceted regulation of ALDH1A1 by Cdk5 in Alzheimer's disease (AD) pathogenesis. ALDH1A1 is a multifunctional enzyme with dehydrogenase, esterase, and anti-oxidant activities. ALDH1A1 is also a major regulator of retinoic acid (RA) signaling, which is critical for normal brain homeostasis. We identified ALDH1A1 as both physiological and pathological target of Cdk5. First, under neurotoxic conditions, Cdk5-induced oxidative stress upregulates ALDH1A1 transcription. Second, Cdk5 increases ALDH1A1 levels by preventing its ubiquitylation via direct phosphorylation. Third, ALDH1A1 phosphorylation increases its dehydrogenase activity by altering its tetrameric state to a highly active monomeric state. Fourth, persistent oxidative stress triggered by deregulated Cdk5 inactivates ALDH1A1. Thus, initially, the good Cdk5 attempts to mitigate ensuing oxidative stress by upregulating ALDH1A1 via phosphorylation and paradoxically by increasing oxidative stress. Later, sustained oxidative stress generated by Cdk5 inhibits ALDH1A1 activity, leading to neurotoxicity. ALDH1A1 upregulation is highly neuroprotective. In human AD tissues, ALDH1A1 levels increase with disease severity. However, ALDH1A1 activity was highest at mild and moderate stages, but declines significantly at severe stage. These findings confirm that during the initial stages, neurons attempt to upregulate and activate ALDH1A1 to protect from accruing oxidative stress-induced damage; however, persistently deleterious conditions inactivate ALDH1A1, further contributing to neurotoxicity. This study thus revealed two faces of Cdk5, good and bad in neuronal function and survival, with a single substrate, ALDH1A1. The bad Cdk5 prevails in the end, overriding the good Cdk5 act, suggesting that Cdk5 is an effective therapeutic target for AD.

Keywords: ALDH1A1; Alzheimer’s disease; Cdk5; Chemical genetic; Neurodegeneration; Neuroprotection.

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Conflict of interest statement

Competing Interests The authors declare that they have no competing interests.

Figures

Fig. 1
Fig. 1
ALDH1A1 is a disease-specific target of Cdk5. a ALDH1A1 is a direct substrate of Cdk5. Cdk5-p25 complex was subjected to kinase assay with either [32P]ATP alone (lane 2) or with 6× His-ALDH1A1 and [32P]ATP (lane 3) for 15 min. Lane 1 shows ALDH1A1 incubated with [32P]ATP. b Cdk5 and ALDH1A1 associate under neurotoxic conditions in HT22 cells. Cdk5 was immunoprecipitated from either control or glutamate-treated HT22 cells (for 0–6 h), and the association of Cdk5 and ALDH1A1 was analyzed (top panel). Lower panel shows Cdk5 input from total cell lysate. Each experiment was repeated at least three independent times. c Cdk5 and ALDH1A1 association under normal and neurotoxic conditions in HT22 cells. ALDH1A1 was immunoprecipitated from either control or glutamate-treated HT22 cells (for 0–6 h), and the association of ALDH1A1 and Cdk5 analyzed. Lower panel shows ALDH1A1 levels from total cell lysate. d Cdk5 binds ALDH1A1 directly. ALDH1A1 and Cdk5 association was analyzed using recombinant Cdk5 and ALDH1A1 in an in vitro pull-down assay. 6× His-Cdk5 on beads was incubated with ALDH1A1 and their binding analyzed. e Cdk5 and ALDH1A1 bind directly. ALDH1A1 on beads was incubated with recombinant Cdk5 and their binding analyzed in an in vitro pull-down assay. f Glutamate stimulates the association of p35/p25 with ALDH1A1. p35/p25 were immunoprecipitated from either control or glutamate-treated HT22 cells (for 0–6 h), and the association of p35/p25 with ALDH1A1 analyzed. Each experiment was repeated at least three independent times. g Glutamate stimulates association of p35/p25 and ALDH1A1. ALDH1A1 was immunoprecipitated from either control or glutamate-treated HT22 cells (for 0–6 h), and the association of ALDH1A1 and p35/p25 was analyzed. Each experiment was repeated at least three independent times. h ALDH1A1 does not bind with p35 or p25 directly. ALDH1A1 and p35 or p25 association was analyzed using recombinant p35, p25, and ALDH1A1 in an in vitro pull-down assay. Recombinant ALDH1A1 on beads was incubated with 6× His-p35 or 6× His-p25 and binding analyzed. i Cdk5 associates with p35/p25 upon glutamate stimulation. p35/p25 were immunoprecipitated from either control or glutamate-treated HT22 cells (for 0–6 h), and the association of p35/p25 with Cdk5 analyzed. Each experiment was repeated at least three independent times. j Cdk5 associates with p35 and p25 upon glutamate stimulation. k Cdk5 activity increases upon glutamate treatment in HT22 cells. Cdk5 kinase assay was performed as described in the “Materials and Methods” section. Each experiment was repeated at least three independent times. *p < 0.05, compared with untreated HT22 cells
Fig. 2
Fig. 2
Cdk5 promotes nuclear localization of ALDH1A1 upon glutamate stimulation. a Glutamate stimulates nuclear translocation of Cdk5 and ALDH1A1. HT22 cells were treated with glutamate for 0–12 h with or without roscovitine, followed by immunostaining as described in the “Materials and Methods” section. Representative pictures are shown. Scale bar, 20 μm. b Quantification of the subcellular localization of ALDH1A1 in the cell nucleus versus the cytoplasm. The graphs show the mean ± SEM of the relative fluorescence intensity with respect to control cells. *p < 0.05 versus nucleus fraction control analyzed by two-way analysis of variance. c Subcellular fractionation of ALDH1A1 in glutamate-treated HT22 cells in the absence or presence of roscovitine as described in the “Materials and Methods” section. Alpha-tubulin is the cytoplasmic marker and lamin A is the nuclear marker. N nuclear fraction, C cytoplasmic fraction. d Cdk5 knockdown inhibits nuclear translocation of ALDH1A1. HT22 cells were treated with Cdk5 shRNA for 30 h, followed by glutamate treatment for 1.5–12 h. e Quantification of the subcellular localization of ALDH1A1 in the cell nucleus versus the cytoplasm. The graphs show the mean ± SEM of the relative fluorescence intensity with respect to control cells. f Cdk5 shRNA-infected HT22 cells were treated with glutamate and fractionated as described in the “Materials and Methods” section. Alpha-tubulin is the cytoplasmic marker and lamin A is the nuclear marker. N nuclear fraction, C cytoplasmic fraction
Fig. 3
Fig. 3
Cdk5 directly phosphorylates ALDH1A1 at S75 and S274. a The Cdk5-p25 complex (Cdk5/p25) phosphorylates ALDH1A1 at S75 and S274. Recombinant 6× His-tagged wild-type and ALDH1A1 mutants were subjected to a kinase assay with Cdk5-p25. b S75 and S274 are the only Cdk5 sites on ALDH1A1, as the 2A-ALDH1A1 mutant is not phosphorylated by Cdk5. c Glutamate stimulates nuclear translocation of Cdk5 and ALDH1A1 in ALDH1A1-HT22 cells. ALDH1A1-HT22 cells were treated with glutamate for 0–12 h with or without roscovitine, followed by immunostaining with anti-HA and Cdk5 antibody. Representative pictures are shown. d Quantification of the subcellular localization of ALDH1A1 in the cell nucleus versus the cytoplasm. The graphs show the mean ± SEM of the relative fluorescence intensity with respect to control cells. *p < 0.05 versus nucleus fraction control analyzed by two-way analysis of variance. e Subcellular fractionation of ALDH1A1 in glutamate-treated ALDH1A1-HT22 cells in the absence or presence of roscovitine. Alpha-tubulin is the cytoplasmic marker and lamin A is the nuclear marker. N nuclear fraction, C cytoplasmic fraction. f Cdk5 knockdown inhibits nuclear translocation of ALDH1A1. Cdk5-shRNA-infected ALDH1A1-HT22 cells were treated with glutamate. Representative pictures are shown. g Quantification of the subcellular localization of ALDH1A1 in the cell nucleus versus the cytoplasm. The graphs show the mean ± SEM of the relative fluorescence intensity with respect to control cells
Fig. 4
Fig. 4
ALDH1A1 translocation to the nucleus is phosphorylation-independent. a 2A-ALDH1A1-HT22 cells were treated with glutamate for 0–12 h, followed by immunostaining with anti-HA antibody. Representative pictures are shown. b Quantification of the subcellular localization of Cdk5 in the cell nucleus versus the cytoplasm. The graphs show the mean ± SEM of the relative fluorescence intensity with respect to control cells. *p < 0.05 versus nucleus fraction control analyzed by two-way analysis of variance. c Quantification of the subcellular localization of ALDH1A1 in the cell nucleus versus the cytoplasm. The graphs show the mean ± SEM of the relative fluorescence intensity with respect to control cells. *p < 0.05 versus nucleus fraction control analyzed by two-way analysis of variance. d Subcellular fractionation of 2A-ALDH1A1 in glutamate-treated 2A-ALDH1A1-HT22 cells. 2A-ALDH1A1 was visualized using anti-HA antibody. Alpha-tubulin is the cytoplasmic marker and lamin A is the nuclear marker. N nuclear fraction, C cytoplasmic fraction. e HT22 cells were treated with glutamate and Cdk5 shRNA and total mRNA levels of ALDH1A1 were detected by real-time qPCR. Expression levels are normalized to the expression of actin. Results are mean ± SEM of three independent experiments. *p <0.05, compared with untreated HT22 cells.#p < 0.05, compared with only glutamate-treated HT22 cells. f HT22 cells were treated with glutamate for 0–24 h and the total levels of ALDH1A1 analyzed. g Average relative ratios of ALDH1A1 band intensities to alpha-tubulin band intensities upon glutamate treatment as obtained from three independent experiments. *p < 0.05, compared with untreated HT22 cells. h HT22 cells were treated with glutamate for 12 h, in the presence and absence of roscovitine or Cdk5 shRNA, and then, the total levels of ALDH1A1 were analyzed. i ALDH1A1 protein levels in HT22 cells in response to glutamate treatment with or without roscovitine and Cdk5 shRNA. Graphical results are mean ± SEM of three independent experiments. *p < 0.05, compared with untreated HT22 cells.#p < 0.05, compared with only glutamate-treated HT22 cells. j ALDH1A1-HT22 cells were treated similarly as in h and the ALDH1A1 levels analyzed. k ALDH1A1 protein levels in ALDH1A1-HT22 cells in response to glutamate treatment with or without roscovitine and Cdk5 shRNA. Graphical results are mean ± SEM of three independent experiments. *p < 0.05, compared with untreated ALDH1A1-HT22 cells, and p < 0.05, compared with only glutamate-treated HT22 cells. l 2A-ALDH1A1-HT22 cells were treated similarly as in f and total levels of ALDH1A1 analyzed. m Average relative ratios of HA (ALDH1A1) band intensities to alpha-tubulin band intensities upon glutamate treatment as obtained from three independent experiments. *p < 0.05, compared with untreated 2A-ALDH1A1-HT22 cells. n 2A-ALDH1A1-HT22 cells were treated similarly as in h and the ALDH1A1 levels analyzed. o ALDH1A1 protein levels in HT22 cells in response to glutamate treatment with or without roscovitine and Cdk5 shRNA. Graphical results are mean ± SEM of three independent experiments. *p < 0.05, compared with untreated 2A-ALDH1A1-HT22 cells
Fig. 5
Fig. 5
Cdk5-mediated phosphorylation of ALDH1A1 modulates its oligomeric state and dehydrogenase activity. a Monomeric ALDH1A1 displaying Cdk5 phosphorylation sites. S75 is present within the NAD+ binding pocket (shown in cyan) and S274 is part of the catalytic site (highlighted in yellow). b Cdk5 increases ALDH1A1 enzymatic activity. Comparative spectrophotometric analysis of ALDH1A1 activity upon phosphorylation by Cdk5. ALDH1A1 activities with and without ATP and Cdk5 were used as controls. c Dephosphorylation of ALDH1A1 by calf-intestinal alkaline phosphatase (CIP) decreases its dehydrogenase activity. Each experiment was done at least three independent times. Representative data are shown. d ALDH1A1-phosphorylation-dead mutant have minimal enzymatic activity. e Phosphorylation of ALDH1A1 by Cdk5 triggers ALDH1A1 oligomers to dissociate to the monomeric form. f Average relative changes in tetramer and monomer abundance derived from three independent experiments. The intensities of tetramer and monomer at each time were normalized independently against time 0. *p < 0.05 versus monomer and#p < 0.05 versus tetramer at 15 and 30 min, respectively, from three independent experiments. g Average ratio of normalized monomer to tetramer as a function of time. To account for the large difference in tetramer and monomer abundance, the intensity of each band was normalized against the tetramer intensity at time zero and the ratio of monomer to tetramer was plotted as a function of time (*p < 0.05 at 15 and 30 min). h Activity staining of phosphorylation-induced ALDH1A1 monomer harbors high dehydrogenase activity. i Coomassie G-250 stain of h. j Quantification of oligomer-specific ALDH1A1 activity from three independent experiments (*p < 0.05 at 15 and 30 min) analyzed by two-way analysis of variance. Specifically, monomer and tetramer intensities of activity and Coomassie stain at 15 and 30 min of phosphorylation were normalized against the unphosphorylated tetramer control (basal activity); then, the normalized activity of each oligomer was divided by its respective normalized Coomassie signal to generate the plot. k Phos-tag staining of phosphorylated ALDH1A1 separated using native gel. l Coomassie G-250 stain of k. m Quantification of normalized Phos-tag intensities with respect to total protein levels from three independent experiments. Protein quantification was carried out in the same way as described for the activity assay (*p < 0.05 for monomer at 0 and 30 min analyzed by two-way analysis of variance). The green color denotes phosphorylation-specific signal
Fig. 6
Fig. 6
Upregulation of ALDH1A1 by Cdk5 is initially neuroprotective and finally neurodegenerative. a Cdk5 depletion provides neuroprotection upon glutamate exposure. Scrambled-shRNA-infected Cdk5-shRNA- or ALDH1A1-shRNA-infected or roscovitine-exposed HT22 cells were treated with glutamate for 24 h. Cell viability was examined using an MTT assay. *p < 0.05, compared with untreated HT22 cells. b ALDH1A1 overexpression rescue cells from glutamate-induced neurotoxicity. HT22, ALDH1A1-HT22, and 2A-ALDH1A1-HT22 cells were treated with glutamate, roscovitine, and Cdk5 shRNA and cell viability tested by using an MTT assay. c Glutamate treatment increased ALDH1A1 activity in HT22 cells while the phosphorylation-resistant mutant cells have diminished enzymatic activity. HT22 and 2A-ALDH1A1-HT22 cells were treated with glutamate for 12 and 24 h. ALDH1A1 was immunoprecipitated using ALDH1A1 and HA antibody, respectively, and enzyme activity was performed as described in the “Materials and Methods” section. d Cdk5 depletion partially prevents the increase in ALDH1A1 activity in 12-h glutamate-treated cells, but rescues ~50% of the decrease in ALDH1A1 activity in 24-h glutamate-treated cells. HT22- and Cdk5-shRNA-treated-HT22 cells were exposed to glutamate for 12 and 24 h. ALDH1A1 was isolated and its activity analyzed. e Elimination of oxidative stress restores ALDH1A1 activity to a significant extent. First set of HT22 cells was treated with glutamate for 12 and 24 h. Second set was pretreated with glutamate for 12 and 16 h, followed by treatment with 200-nM TAT-fused peroxiredoxin-II-T89A for the next 12 and 8 h, respectively. TAT-fused peroxiredoxin-II-T89A protein was purified fresh and added every 4 h. TAT-fusion red fluorescent protein (TAT-RFP) was used as a control. ALDH1A1 immune complex was isolated and its dehydrogenase activity determined as described in the “Materials and Methods” section. f DTT treatment is beneficial for ALDH1A1 enzymatic activity initially. HT22 cells were treated with glutamate for 12 and 24 h. ALDH1A1 was immunoprecipitated using ALDH1A1 antibody, and enzyme activity was performed with or without 10 mM DTT in reaction buffers as described in the “Materials and Methods” section. g Eliminating oxidative stress affects ALDH1A1 level. HT22 cells were treated as described in e and ALDH1A1 levels analyzed. h ALDH1A1 protein levels in HT22 cells in response to glutamate treatment with or without TAT-Prx-II (T89A) pretreatment. Graphical results are mean ± SEM of three independent experiments. *p < 0.05, compared with untreated HT22 cells, and#p < 0.05, compared with only glutamate-treated HT22 cells. i Exposure to sub-lethal concentration of H2O2 increases ALDH1A1 protein levels. HT22 cells were treated with varying concentrations of H2O2 for 12 h and ALDH1A1 levels analyzed. j ALDH1A1 mRNA increases on exposure to glutamate treatment. HT22 cells were exposed to 5 mM glutamate and ALDH1A1 mRNA levels analyzed using semi-quantitative PCR after 12 and 24 h of treatments. k ALDH1A1 mRNA levels in HT22 cells in response to glutamate treatment for 12 and 24 h. Graphical results are mean ± SEM of three independent experiments. *p < 0.05, compared with untreated HT22 cells. l Exposure to sub-lethal concentration of H2O2 increases ALDH1A1 mRNA levels in HT22 cells. m Exposure to sub-lethal concentration of H2O2 increases ALDH1A1 mRNA levels. Graphical results are mean ± SEM of three independent experiments. *p < 0.05, compared with untreated HT22 cells. n Glutamate exposure decreases ALDH1A1 ubiquitylation in a Cdk5-dependent manner. 6× His ubiquitin was expressed in HT22 cells, followed by glutamate treatment for 12 h in the presence and absence of Cdk5 shRNA. ALDH1A1 was immunoprecipitated and potential ubiquitylation analyzed using 6× His antibody. Each experiment was done at least three independent times. Representative data are shown. o HA-tagged wild-type ALDH1A1 displays less ubiquitylation in response to glutamate treatment. HA-ALDH1A1-HT22 cells were treated similarly as described above, and ubiquitylated proteins were isolated using HA antibody and analyzed. Each experiment was done at least three independent times. Representative data are shown. p 2A-ALDH1A1 is resistant to Cdk5-dependent protection to ubiquitylation. 2A-ALDH1A1-HT22 cells were treated similarly, and ubiquitylated proteins were isolated using HA antibody and analyzed. Each experiment was done at least three independent times. Representative data are shown
Fig. 7
Fig. 7
Cdk5-ALDH1A1 signaling in primary neurons. a Inhibition and ablation of Cdk5 inhibits neurotoxicity in primary cortical neurons. Cdk5-shRNA-infected primary neurons (30 h) were treated with glutamate (24 h). Cell viability was tested by an MTT assay. *p < 0.05, compared with untreated neurons. b Overexpression of ALDH1A1 prevents neurotoxicity in primary cortical neurons. ALDH1A1 overexpressed primary neurons (30 h) were treated with glutamate (24 h). Cell viability was tested by MTT assay. *p < 0.05, compared with untreated neurons. c Glutamate exposure triggers nuclear translocation of ALDH1A1 in a Cdk5-dependent manner. Primary cortical neurons were treated with glutamate (100 μM) for 12 h in the presence or absence of roscovitine (10 μM), followed by immunostaining with Cdk5 and ALDH1A1 antibodies. d Quantification of the subcellular localization of ALDH1A1 in the cell nucleus versus the cytoplasm. The graphs show the mean ± SEM of the relative fluorescence intensity with respect to control cells. *p < 0.05 versus nucleus fraction control analyzed by two-way analysis of variance. e Cdk5 depletion inhibits nuclear translocation of ALDH1A1. Primary cortical neurons were treated with glutamate (100 μM) for 12 h in the presence or absence of Cdk5 shRNA, followed by immunostaining with Cdk5 and ALDH1A1 antibodies. f Primary cortical neurons were treated with glutamate for 12 and 24 h, in the presence and absence of Cdk5 shRNA, and then, the total levels of ALDH1A1 mRNA were analyzed using semi-quantitative RT-PCR. g ALDH1A1 mRNA levels in primary cortical neurons in response to glutamate treatment with or without Cdk5 shRNA. Graphical results are mean ± SEM of three independent experiments. *p < 0.05, compared with untreated primary cortical neurons.#p < 0.05, compared with only glutamate-treated neurons. h Primary cortical neurons were treated similarly as described for f, g, and total mRNA levels of ALDH1A1 were detected by real-time qPCR. Expression levels are normalized to the expression of actin. Results are mean ± SEM of three independent experiments. *p < 0.05, compared with untreated neurons.#p < 0.05, compared with only glutamate-treated neurons. i Glutamate treatment increases ALDH1A1 protein levels in primary cortical neurons in a time-dependent manner. Primary cortical neurons were treated with glutamate for 0–24 h and the total levels of ALDH1A1 analyzed. j Average relative ratios of ALDH1A1 band intensities to alpha-tubulin band intensities upon glutamate treatment as obtained from three independent experiments. *p < 0.05, compared with untreated primary neurons. k Glutamate treatment increases ALDH1A1 protein levels in primary cortical neurons in a Cdk5-dependent manner. ALDH1A1 levels were analyzed upon glutamate (12 h), roscovitine, and Cdk5 shRNA treatments. l ALDH1A1 protein levels in primary cortical neurons in response to glutamate treatment with or without roscovitine and Cdk5 shRNA. Graphical results are mean ± SEM of three independent experiments. *p < 0.05, compared with untreated primary neurons, and#p < 0.05, compared with only glutamate-treated primary neurons. m ALDH1A1 enzyme activity in primary cortical neurons in response to glutamate treatment with or without Cdk5 shRNA. n Removal of oxidative stress restores ALDH1A1 activity to a significant extent. Primary cortical neurons were either treated with glutamate for 12 and 24 h or were pretreated with glutamate for 12 and 16 h, followed by subsequent treatment with 200-nM TAT-fused peroxiredoxin-II-T89A for the next 12 and 8 h, respectively. TAT-fused peroxiredoxin-II-T89A protein was purified fresh and added every 4 h. TAT-fusion red fluorescent protein (TAT-RFP) was used as a control. ALDH1A1 immune complex was isolated, and its dehydrogenase activity was determined as described in the “Materials and Methods” section. o DTT treatment is beneficial for ALDH1A1 enzymatic activity initially. Primary cortical neuron cells were treated with glutamate for 12 and 24 h. ALDH1A1 was immunoprecipitated using ALDH1A1 antibody, and enzyme activity was performed with or without 10 mM DTT in reaction buffers as described in the “Materials and Methods” section
Fig. 8
Fig. 8
ALDH1A1 levels and activity are independently regulated in AD clinical specimens. a Cdk5 kinase activity in primary cortical neurons at DIV1, DIV6, and DIV13. Cdk5 kinase assay was performed as described in the “Materials and Methods” section. Each experiment was repeated at least three independent times. *p < 0.05, compared with DIV1. b Cdk5, p35, and ALDH1A1 levels in DIV6 and DIV14 primary neurons in presence and absence of Cdk5 shRNA. The experiment was repeated two independent times, and a representative picture is presented. c ALDH1A1 levels in human AD and age-matched control brain tissues (cohort 1). ALDH1A1 levels were analyzed in tissues obtained from AD patients at mild (n = 1), moderate stage (n = 2), and severe stage (n = 2) along with age-matched controls (n = 3). d Average ALDH1A1 levels in age-matched controls and AD specimens from three independent experiments. e ALDH1A1 enzyme activity in age-matched controls and AD specimens from three independent experiments. f Same data as in Fig. 8e displaying relative ALDH1A1 activity at 90 min in age-matched controls and AD specimens from three independent experiments. g ALDH1A1 levels in human AD and age-matched control brain tissues (cohort 2; Table 1). h Average ALDH1A1 levels in age-matched controls and AD specimens from three independent experiments from cohort 2. i ALDH1A1 enzyme activity in age-matched controls and AD specimens from three independent experiments at 90 min from cohort 2. j Our model showing Cdk5’s contribution to ALDH1A1-mediated signaling under physiological and pathological conditions. Under physiological conditions, Cdk5 associates with p35, which activates it resulting in upregulation of ALDH1A1, which is neuroprotective. Upon neurotoxic conditions, Cdk5 initially plays a neuroprotective role by activating and upregulating ALDH1A1. Glutamate stimulation triggers the formation of p25 formation, which hyperactivates Cdk5, leading to the phosphorylation of ALDH1A1 and subsequent increase in ALDH1A1 levels and activity. However, later, Cdk5-induced oxidative stress inhibits ALDH1A1 activity rendering it ineffective, resulting in neurotoxicity
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