5-HT4 receptor agonists treatment reduces tau pathology and behavioral deficit in the PS19 mouse model of tauopathy.

Background: Accumulation of tau in synapses in the early stages of Alzheimer's disease (AD) has been shown to cause synaptic damage, synaptic loss, and the spread of tau pathology through trans-synaptically connected neurons. Moreover, synaptic loss correlates with a decline in cognitive function, providing an opportunity to investigate therapeutic strategies to target synapses and synaptic tau to rescue or prevent cognitive decline in AD. One of the promising synaptic targets is the 5-HT4 serotonergic receptor present postsynaptically in the brain structures involved in the memory processes. 5-HT4R stimulation exerts synaptogenic and pro-cognitive effects involving synapse-to-nucleus signaling essential for synaptic plasticity. However, it is not known whether 5-HT4R activation has a therapeutic effect on tau pathology. Methods: The goal of this study was to investigate the impact of chronic stimulation of 5-HT4R by two agonists, prucalopride and RS-67333, in PS19 mice, a model of tauopathy. We utilized gradient assays to isolate pre- and post-synaptic compartments, followed by biochemical analyses for tau species and ubiquitinated proteins in the synaptic compartments and total brain tissue. Next, we performed kinetic assays to test the proteasome's hydrolysis capacity in treatment conditions. Moreover, behavioral tests such as the open field and non-maternal nest-building tests were used to evaluate anxiety-like behaviors and hippocampal-related cognitive functioning in the treatment paradigm. Results: Our results show that 5-HT4R agonism reduced tauopathy, reduced synaptic tau, increased proteasome activity, and improved cognitive functioning in PS19 mice. Our data suggest that enhanced proteasome activity by synaptic mediated signaling leads to the enhanced turnover of tau initially within synapses where the receptors are localized, and over time, the treatment attenuated the accumulation of tau aggregation and improved cognitive functioning of the PS19 mice. Conclusion: Therefore, stimulation of 5-HT4R offers a promising therapy to rescue synapses from the accumulation of toxic synaptic tau, evident in the early stages of AD.

Fractional Factorial Design to Evaluate the Synthesis and Electrochemical Transfer Parameters of h-BN Coatings.

In this study, we present a fractional factorial design approach for exploring the effects and interactions of key synthesis and electrochemical transfer parameters on the roughness and wettability of hexagonal boron nitride (h-BN) coatings, due to their essential role in biofilm formation. The studied parameters for the synthesis process include precursor mass, growth time, and substrate conditioning, whereas for the transfer process, applied voltage and aqueous medium concentration were studied. Through this polynomial model, we confirmed the strong influence of precursor mass and medium concentration parameters on h-BN surface roughness and its resulting antibiofilm properties.

5-HT4 receptor agonists treatment reduces tau pathology and behavioral deficit in the PS19 mouse model of tauopathy.

Accumulation of tau in synapses in Alzheimer’s disease (AD) has been shown to cause synaptic damage, synaptic loss, and the spread of pathology through synaptically connected neurons. Synaptic loss correlates with a decline in cognition, providing an opportunity to investigate strategies to target synaptic tau to rescue or prevent cognitive decline. One of the promising synaptic targets is the 5-HT4 receptor present post-synaptically in the brain areas involved in the memory processes. 5-HT4R activation exerts synaptogenic and pro-cognitive effects involving synapse-to-nucleus signaling essential for synaptic plasticity. However, it is not known whether 5-HT4R activation has a therapeutic effect on tauopathy. The goal of this study was to investigate the impact of stimulation of 5-HT4R in tauopathy mice. Our results show that 5-HT4R agonism led to reduced tauopathy and synaptic tau and correlated with increased proteasome activity and improved cognitive functioning in PS19 mice. Thus, stimulation of 5-HT4R offers a promising therapy to rescue synapses from toxic synaptic tau.

Mental and behavioral disorders in the prison context.

INTRODUCTION: During the execution of sentences in prison units, there are deficiencies within the adaptation mechanisms of persons deprived of liberty, this varies depending on the place where they serve the sanction and the length of stay in it. OBJECTIVES: To collect information on the prevalence of mental and behavioural disorders in the prison setting, as well as the importance of early psychiatric intervention. MATERIAL AND METHOD: Theoretical review. Primary sources of information: scientific articles from indexed journals, in specialized medical information search engines. Original publications on mental and behavioural disorders in the prison and prison context were included, from 2016 to April 2021, with an analytical, observational, prospective, retrospective, cross-sectional and randomized design, systematic reviews and meta-analyzes, complete articles, carried out in any country, with subjects over 15 years of age, of any sex or gender, in English and Spanish. RESULTS: 16 articles were included in this theoretical review. The prevalence of mental disorders within the prison population is high; depression, anxiety, substance use and psychotic disorders predominate. The importance of having mental health programmes in prisons, with initial diagnosis and personalized interventions, was observed. The authors recommend psychopharmacological interventions and cognitive behavioural management. DISCUSSION: The need to restructure the mental health approach in prisons was evidenced, and early diagnosis and personalized follow-up should be guaranteed. Pharmacological intervention and, to a greater degree, cognitive behavioural therapy seem to be effective for these types of patients.

Trastornos mentales y del comportamiento en el contexto carcelario y penitenciario / Mental and behavioral disorders in the prison context

Introducción: Durante el cumplimiento de condenas en unidades carcelarias, existen deficiencias dentro de los mecanismos deadaptación de las personas privadas de la libertad, esto varía dependiendo del lugar donde cumplan la sanción y el tiempo deestancia.Objetivos: Recopilar información sobre la prevalencia de trastornos mentales y del comportamiento en el ámbito carcelario ypenitenciario, así como la importancia de una intervención psiquiátrica temprana.Material y método: Revisión teórica. Fuentes de información primarias: artículos científicos de revistas indexadas, en buscadores de información médica especializados. Se incluyeron publicaciones sobre trastornos mentales y del comportamiento enel contexto carcelario y penitenciario, desde enero del 2016 hasta abril de 2021, originales, con diseño analítico, observacional,prospectivo, retrospectivo, transversal y aleatorizado, revisiones sistemáticas y metaanálisis, artículos completos, realizados encualquier país, con sujetos mayores de 15 años, de cualquier sexo o género, en idioma inglés y español.Resultados: Se incluyeron 16 artículos en esta revisión teórica. La prevalencia de trastornos mentales dentro de la poblaciónpenitenciaria es elevada; predominan los trastornos depresivos, de ansiedad, por consumo de sustancias y psicóticos. Se observóla importancia de contar con programas de salud mental en las instituciones carcelarias, con diagnóstico inicial e intervencionespersonalizadas. Los autores recomiendan intervenciones psicofarmacológicas y manejo cognitivo conductual.Discusión: Se evidenció la necesidad de reestructurar el abordaje en salud mental de los centros carcelarios, garantizando eldiagnóstico precoz y un seguimiento personalizado. La intervención farmacológica y, en mayor grado, la terapia cognitiva conductual parece ser efectivas en este tipo de pacientes. (AU)

Introduction: During the execution of sentences in prison units, there are deficiencies within the adaptation mechanisms ofpersons deprived of liberty, this varies depending on the place where they serve the sanction and the length of stay in it.Objectives: To collect information on the prevalence of mental and behavioural disorders in the prison setting, as well as theimportance of early psychiatric intervention.Material and method: Theoretical review. Primary sources of information: scientific articles from indexed journals, in specialized medical information search engines. Original publications on mental and behavioural disorders in the prison and prisoncontext were included, from 2016 to April 2021, with an analytical, observational, prospective, retrospective, cross-sectionaland randomized design, systematic reviews and meta-analyzes, complete articles, carried out in any country, with subjects over15 years of age, of any sex or gender, in English and Spanish.Results: 16 articles were included in this theoretical review. The prevalence of mental disorders within the prison populationis high; depression, anxiety, substance use and psychotic disorders predominate. The importance of having mental health programmes in prisons, with initial diagnosis and personalized interventions, was observed. The authors recommend psychopharmacological interventions and cognitive behavioural management. Discussion: The need to restructure the mental health approach in prisons was evidenced, and early diagnosis and personalizedfollow-up should be guaranteed. Pharmacological intervention and, to a greater degree, cognitive behavioural therapy seem tobe effective for these types of patients. (AU)

PAC1 receptor-mediated clearance of tau in postsynaptic compartments attenuates tau pathology in mouse brain.

Accumulation of pathological tau in synapses has been identified as an early event in Alzheimer's disease (AD) and correlates with cognitive decline in patients with AD. Tau is a cytosolic axonal protein, but under disease conditions, tau accumulates in postsynaptic compartments and presynaptic terminals, due to missorting within neurons, transsynaptic transfer between neurons, or a failure of clearance pathways. Using subcellular fractionation of brain tissue from rTg4510 tau transgenic mice with tauopathy and human postmortem brain tissue from patients with AD, we found accumulation of seed-competent tau predominantly in postsynaptic compartments. Tau-mediated toxicity in postsynaptic compartments was exacerbated by impaired proteasome activity detected by measuring lysine-48 polyubiquitination of proteins targeted for proteasomal degradation. To combat the accumulation of tau and proteasome impairment in the postsynaptic compartments of rTg4510 mouse brain, we stimulated the pituitary adenylate cyclase-activating polypeptide (PACAP) type 1 receptor (PAC1R) with its ligand PACAP administered intracerebroventricularly to rTg4510 mice. We observed enhanced synaptic proteasome activity and reduced total tau in postsynaptic compartments in mouse brain after PACAP treatment. The clearance of tau from postsynaptic compartments correlated with attenuated tauopathy and improved cognitive performance of rTg4510 transgenic mice on two behavioral tests. These results suggest that activating PAC1R could prevent accumulation of aggregate-prone tau and indicate a potential therapeutic approach for AD and other tauopathies.

Atrophy associated with tau pathology precedes overt cell death in a mouse model of progressive tauopathy.

Tau pathology in Alzheimer's disease (AD) first develops in the entorhinal cortex (EC), then spreads to the hippocampus, followed by the neocortex. Overall, tau pathology correlates well with neurodegeneration and cell loss, but the spatial and temporal association between tau pathology and overt volume loss (atrophy) associated with structural changes or cell loss is unclear. Using in vivo magnetic resonance imaging (MRI) with tensor-based morphometry (TBM), we mapped the spatiotemporal pattern of structural changes in a mouse model of AD-like progressive tauopathy. A novel, coregistered in vivo MRI atlas was then applied to identify regions in the medial temporal lobe that had a significant volume reduction. Our study shows that in a mouse model of tauopathy spread, the propagation of tau pathology from the EC to the hippocampus is associated with TBM-related atrophy, but atrophy in the dentate gyrus and subiculum precedes overt cell loss.

APOE4 is Associated with Differential Regional Vulnerability to Bioenergetic Deficits in Aged APOE Mice.

The ε4 allele of apolipoprotein E (APOE) is the dominant genetic risk factor for late-onset Alzheimer's disease (AD). However, the reason for the association between APOE4 and AD remains unclear. While much of the research has focused on the ability of the apoE4 protein to increase the aggregation and decrease the clearance of Aß, there is also an abundance of data showing that APOE4 negatively impacts many additional processes in the brain, including bioenergetics. In order to gain a more comprehensive understanding of APOE4's role in AD pathogenesis, we performed a transcriptomics analysis of APOE4 vs. APOE3 expression in the entorhinal cortex (EC) and primary visual cortex (PVC) of aged APOE mice. This study revealed EC-specific upregulation of genes related to oxidative phosphorylation (OxPhos). Follow-up analysis utilizing the Seahorse platform showed decreased mitochondrial respiration with age in the hippocampus and cortex of APOE4 vs. APOE3 mice, but not in the EC of these mice. Additional studies, as well as the original transcriptomics data, suggest that multiple bioenergetic pathways are differentially regulated by APOE4 expression in the EC of aged APOE mice in order to increase the mitochondrial coupling efficiency in this region. Given the importance of the EC as one of the first regions to be affected by AD pathology in humans, the observation that the EC is susceptible to differential bioenergetic regulation in response to a metabolic stressor such as APOE4 may point to a causative factor in the pathogenesis of AD.

A tau homeostasis signature is linked with the cellular and regional vulnerability of excitatory neurons to tau pathology.

Excitatory neurons are preferentially impaired in early Alzheimer's disease but the pathways contributing to their relative vulnerability remain largely unknown. Here we report that pathological tau accumulation takes place predominantly in excitatory neurons compared to inhibitory neurons, not only in the entorhinal cortex, a brain region affected in early Alzheimer's disease, but also in areas affected later by the disease. By analyzing RNA transcripts from single-nucleus RNA datasets, we identified a specific tau homeostasis signature of genes differentially expressed in excitatory compared to inhibitory neurons. One of the genes, BCL2-associated athanogene 3 (BAG3), a facilitator of autophagy, was identified as a hub, or master regulator, gene. We verified that reducing BAG3 levels in primary neurons exacerbated pathological tau accumulation, whereas BAG3 overexpression attenuated it. These results define a tau homeostasis signature that underlies the cellular and regional vulnerability of excitatory neurons to tau pathology.

Neuronal hyperactivity due to loss of inhibitory tone in APOE4 mice lacking Alzheimer's disease-like pathology.

The ε4 allele of apolipoprotein E (APOE) is the dominant genetic risk factor for late-onset Alzheimer's disease (AD). However, the reason APOE4 is associated with increased AD risk remains a source of debate. Neuronal hyperactivity is an early phenotype in both AD mouse models and in human AD, which may play a direct role in the pathogenesis of the disease. Here, we have identified an APOE4-associated hyperactivity phenotype in the brains of aged APOE mice using four complimentary techniques-fMRI, in vitro electrophysiology, in vivo electrophysiology, and metabolomics-with the most prominent hyperactivity occurring in the entorhinal cortex. Further analysis revealed that this neuronal hyperactivity is driven by decreased background inhibition caused by reduced responsiveness of excitatory neurons to GABAergic inhibitory inputs. Given the observations of neuronal hyperactivity in prodromal AD, we propose that this APOE4-driven hyperactivity may be a causative factor driving increased risk of AD among APOE4 carriers.

Tau Pathology Induces Excitatory Neuron Loss, Grid Cell Dysfunction, and Spatial Memory Deficits Reminiscent of Early Alzheimer's Disease.

The earliest stages of Alzheimer's disease (AD) are characterized by the formation of mature tangles in the entorhinal cortex and disorientation and confusion when navigating familiar places. The medial entorhinal cortex (MEC) contains specialized neurons called grid cells that form part of the spatial navigation system. Here we show in a transgenic mouse model expressing mutant human tau predominantly in the EC that the formation of mature tangles in old mice was associated with excitatory cell loss and deficits in grid cell function, including destabilized grid fields and reduced firing rates, as well as altered network activity. Overt tau pathology in the aged mice was accompanied by spatial memory deficits. Therefore, tau pathology initiated in the entorhinal cortex could lead to deficits in grid cell firing and underlie the deterioration of spatial cognition seen in human AD.

The Endosomal-Lysosomal Pathway Is Dysregulated by APOE4 Expression in Vivo.

Possession of the ε4 allele of apolipoprotein E (APOE) is the major genetic risk factor for late-onset Alzheimer's disease (AD). Although numerous hypotheses have been proposed, the precise cause of this increased AD risk is not yet known. In order to gain a more comprehensive understanding of APOE4's role in AD, we performed RNA-sequencing on an AD-vulnerable vs. an AD-resistant brain region from aged APOE targeted replacement mice. This transcriptomics analysis revealed a significant enrichment of genes involved in endosomal-lysosomal processing, suggesting an APOE4-specific endosomal-lysosomal pathway dysregulation in the brains of APOE4 mice. Further analysis revealed clear differences in the morphology of endosomal-lysosomal compartments, including an age-dependent increase in the number and size of early endosomes in APOE4 mice. These findings directly link the APOE4 genotype to endosomal-lysosomal dysregulation in an in vivo, AD pathology-free setting, which may play a causative role in the increased incidence of AD among APOE4 carriers.

3D Visualization of the Temporal and Spatial Spread of Tau Pathology Reveals Extensive Sites of Tau Accumulation Associated with Neuronal Loss and Recognition Memory Deficit in Aged Tau Transgenic Mice.

3D volume imaging using iDISCO+ was applied to observe the spatial and temporal progression of tau pathology in deep structures of the brain of a mouse model that recapitulates the earliest stages of Alzheimer's disease (AD). Tau pathology was compared at four timepoints, up to 34 months as it spread through the hippocampal formation and out into the neocortex along an anatomically connected route. Tau pathology was associated with significant gliosis. No evidence for uptake and accumulation of tau by glia was observed. Neuronal cells did appear to have internalized tau, including in extrahippocampal areas as a small proportion of cells that had accumulated human tau protein did not express detectible levels of human tau mRNA. At the oldest timepoint, mature tau pathology in the entorhinal cortex (EC) was associated with significant cell loss. As in human AD, mature tau pathology in the EC and the presence of tau pathology in the neocortex correlated with cognitive impairment. 3D volume imaging is an ideal technique to easily monitor the spread of pathology over time in models of disease progression.

Small misfolded Tau species are internalized via bulk endocytosis and anterogradely and retrogradely transported in neurons.

The accumulation of Tau into aggregates is associated with key pathological events in frontotemporal lobe degeneration (FTD-Tau) and Alzheimer disease (AD). Recent data have shown that misfolded Tau can be internalized by cells in vitro (Frost, B., Jacks, R. L., and Diamond, M. I. (2009) J. Biol. Chem. 284, 12845-12852) and propagate pathology in vivo (Clavaguera, F., Bolmont, T., Crowther, R. A., Abramowski, D., Frank, S., Probst, A., Fraser, G., Stalder, A. K., Beibel, M., Staufenbiel, M., Jucker, M., Goedert, M., and Tolnay, M. (2009) Nat. Cell Biol. 11, 909-913; Lasagna-Reeves, C. A., Castillo-Carranza, D. L., Sengupta, U., Guerrero-Munoz, M. J., Kiritoshi, T., Neugebauer, V., Jackson, G. R., and Kayed, R. (2012) Sci. Rep. 2, 700). Here we show that recombinant Tau misfolds into low molecular weight (LMW) aggregates prior to assembly into fibrils, and both extracellular LMW Tau aggregates and short fibrils, but not monomers, long fibrils, nor long filaments purified from brain extract are taken up by neurons. Remarkably, misfolded Tau can be internalized at the somatodendritic compartment, or the axon terminals and it can be transported anterogradely, retrogradely, and can enhance tauopathy in vivo. The internalized Tau aggregates co-localize with dextran, a bulk-endocytosis marker, and with the endolysosomal compartments. Our findings demonstrate that exogenous Tau can be taken up by cells, uptake depends on both the conformation and size of the Tau aggregates and once inside cells, Tau can be transported. These data provide support for observations that tauopathy can spread trans-synaptically in vivo, via cell-to-cell transfer.

Metabolic activity determines efficacy of macroautophagic clearance of pathological oligomeric alpha-synuclein.

Macroautophagy is an essential degradative pathway that can be induced to clear aggregated proteins, such as those found in Parkinson's disease and dementia with Lewy bodies, a form of Parkinsonism. This study found that both LC3-II and beclin were significantly increased in brains from humans with Dementia with Lewy bodies and transgenic mice overexpressing mutant alpha-synuclein, as compared with respective controls, suggesting that macroautophagy is induced to remove alpha-syn, particularly oligomeric or mutant forms. Aged mutant animals had higher autophagy biomarker levels relative to younger animals, suggesting that with aging, autophagy is less efficient and requires more stimulation to achieve the same outcome. Disruption of autophagy by RNA interference significantly increased alpha-syn oligomer accumulation in vitro, confirming the significance of autophagy in alpha-syn clearance. Finally, rotenone-induced alpha-syn aggregates were cleared following rapamycin stimulation of autophagy. Chronic rotenone exposure and commensurate reduction of metabolic activity limited the efficacy of rapamycin to promote autophagy, suggesting that cellular metabolism is critical for determining autophagic activity. Cumulatively, these findings support the concept that neuronal autophagy is essential for protein homeostasis and, in our system, reduction of autophagy increased the accumulation of potentially pathogenic alpha-synuclein oligomers. Aging and metabolic state were identified as important determinants of autophagic activity. This study provides therapeutic and pathological implications for both synucleinopathy and Parkinson's disease, identifying conditions in which autophagy may be insufficient to degrade alpha-syn aggregates.

Anesthesia-induced hyperphosphorylation detaches 3-repeat tau from microtubules without affecting their stability in vivo.

In Alzheimer's disease, tau is hyperphosphorylated, which is thought to detach it from microtubules (MTs), induce MT destabilization, and promote aggregation. Using a previously described in vivo model, we investigated whether hyperphosphorylation impacts tau function in wild-type and transgenic mice. We found that after anesthesia-induced hypothermia, MT-free tau was hyperphosphorylated, which impaired its ability to bind MTs and promote MT assembly. MT-bound tau was more resistant to hyperphosphorylation compared with free tau and tau did not dissociate from MTs in wild-type mice. However, 3-repeat tau detached from MT in the transgenic mice. Surprisingly, dissociation of tau from MTs did not lead to overt depolymerization of tubulin, and there was no collapse, or disturbance of axonal MT networks. These results indicate that, in vivo, a subpopulation of tau bound to MTs does not easily dissociate under conditions that extensively phosphorylate tau. Tau remaining on the MTs under these conditions is sufficient to maintain MT network integrity.

A transgenic rat that develops Alzheimer's disease-like amyloid pathology, deficits in synaptic plasticity and cognitive impairment.

In the last decade, multiple lines of transgenic APP overexpressing mice have been created that recapitulate certain aspects of Alzheimer's disease (AD). However, none of the previously reported transgenic APP overexpressing rat models developed AD-like beta-amyloid (Abeta) deposits, or age-related learning and memory deficits. In the present study, we have characterized a transgenic rat model overexpressing transgenes with three, familial AD mutations (two in APP and one in PS1) that were developed by Flood et al. [Flood, D.G., et al., Abeta deposition in a transgenic rat model of Alzheimer's disease. Society for Neuroscience 2003, Washington, DC, 2003]. From the age of 9 months, these rats develop Abeta deposits in both diffuse and compact forms, with the latter being closely associated with activated microglia and reactive astrocytes. Impaired long-term potentiation (LTP) was revealed by electrophysiological recordings performed on hippocampal slices from rats at 7 months of age, which is 2 months before the appearance of amyloid plaques. The deficit in LTP was accompanied by impaired spatial learning and memory in the Morris water maze, which became more pronounced in transgenic rats of 13 months of age. For Tg rats of both ages, there was a trend for cognitive impairment to correlate with total Abeta42 levels in the hippocampus. The rat model therefore recapitulates AD-like amyloid pathology and cognitive impairment. The advantage of the rat model over the available mouse models is that rats provide better opportunities for advanced studies, such as serial CSF sampling, electrophysiology, neuroimaging, cell-based transplant manipulations, and complex behavioral testing.

Transcriptional regulation of beta-secretase by p25/cdk5 leads to enhanced amyloidogenic processing.

Cyclin-dependent kinase 5 (cdk5) has been implicated in Alzheimer's disease (AD) pathogenesis. Here, we demonstrate that overexpression of p25, an activator of cdk5, led to increased levels of BACE1 mRNA and protein in vitro and in vivo. A p25/cdk5 responsive region containing multiple sites for signal transducer and activator of transcription (STAT1/3) was identified in the BACE1 promoter. STAT3 interacts with the BACE1 promoter, and p25-overexpressing mice had elevated levels of pSTAT3 and BACE1, whereas cdk5-deficient mice had reduced levels. Furthermore, mice with a targeted mutation in the STAT3 cdk5 responsive site had lower levels of BACE1. Increased BACE levels in p25 overexpressing mice correlated with enhanced amyloidogenic processing that could be reversed by a cdk5 inhibitor. These data demonstrate a pathway by which p25/cdk5 increases the amyloidogenic processing of APP through STAT3-mediated transcriptional control of BACE1 that could have implications for AD pathogenesis.

Interplay between cyclin-dependent kinase 5 and glycogen synthase kinase 3 beta mediated by neuregulin signaling leads to differential effects on tau phosphorylation and amyloid precursor protein processing.

Cyclin-dependent kinase 5 (cdk5) and glycogen synthase kinase 3beta (GSK3beta) have been implicated in pathogenic processes associated with Alzheimer's disease because both kinases regulate tau hyperphosphorylation and enhance amyloid precursor protein (APP) processing leading to an increase in amyloid beta (Abeta) production. Here we show that young p25 overexpressing mice have enhanced cdk5 activity but reduced GSK3beta activity attributable to phosphorylation at the inhibitory GSK3beta-serine 9 (GSK3beta-S9) site. Phosphorylation at this site was mediated by enhanced activity of the neuregulin receptor complex, ErbB, and activation of the downstream phosphatidylinositol 3 kinase/Akt pathway. Young p25 mice had elevated Abeta peptide levels, but phospho-tau levels were decreased overall. Thus, cdk5 appears to play a dominant role in the regulation of amyloidogenic APP processing, whereas GSK3beta plays a dominant role in overall tau phosphorylation. In older mice, GSK3beta inhibitory phosphorylation at S9 was reduced relative to young mice. Abeta peptide levels were still elevated but phospho-tau levels were either unchanged or showed a trend to increase, suggesting that GSK3beta activity increases with aging. Inhibition of cdk5 by a specific inhibitor reduced cdk5 activity in p25 mice, leading to reduced Abeta production in both young and old mice. However, in young mice, cdk5 inhibition reversed GSK3beta inhibition, leading to an increase in overall tau phosphorylation. When cdk5 inhibitor was administered to very old, nontransgenic mice, inhibition of cdk5 reduced Abeta levels, and phospho-tau levels showed a trend to increase. Thus, cdk5 inhibitors may not be effective in targeting tau phosphorylation in the elderly.