Alzheimer’s disease (AD) is increasingly associated with alterations in cholesterol metabolism. Proprotein convertase subtilisin/kexin type 9 (PCSK9), an enzyme regulating low-density lipoprotein receptor (LDLR) degradation, has been implicated in AD through mechanisms involving amyloid-β (Aβ) processing, tau phosphorylation, and synaptic dysfunction. This review aimed to evaluate clinical, genetic, and experimental evidence regarding the role of PCSK9 in AD and its potential as a biomarker or therapeutic target. A systematic search was conducted in PubMed, Scopus, ScienceDirect, and Google Scholar (2020–2025) using predefined terms related to PCSK9 and Alzheimer’s disease. Eligible studies included clinical, in vivo, and in vitro investigations reporting PCSK9 expression, regulation, or inhibition in relation to AD pathology. Due to methodological heterogeneity, a narrative synthesis was performed. Forty-two studies met inclusion criteria. Preclinical findings consistently showed that elevated PCSK9 may indirectly promote Aβ accumulation, tau hyperphosphorylation, neuroinflammation, and cognitive decline, while genetic deletion or pharmacological inhibition of PCSK9 mitigates these effects. Clinical evidence was variable: several studies identified increased PCSK9 levels in cerebrospinal fluid or brain tissue of AD patients, often correlating with tau markers, but large-scale genetic and Mendelian randomization studies did not confirm a causal association. PCSK9 inhibitors, widely used in cardiovascular therapy, demonstrated potent LDL-C reduction without cognitive adverse effects. Experimental data suggest that PCSK9 contributes to AD-related pathology, whereas human evidence indicates a modulatory or biomarker role rather than a causative one. Despite strong preclinical data, human genetics lacks causal evidence for PCSK9 in Alzheimer’s. It may be a disease modifier or biomarker; its clinical relevance requires confirmation through longitudinal studies and CNS-penetrant therapies.

Disrupted proteostasis and ionic imbalance in TDP-43 and tauopathies: Dual drivers of neurodegeneration.

EAAT2 dysfunction mediates acrylamide-induced excitotoxicity and neuronal damage in a SH-SY5Y/U251 co-culture model.

Calcium dysregulation in Alzheimer's disease: unraveling the molecular nexus of neuronal dysfunction and therapeutic opportunities.

CB1 receptor activation and inhibition differentially modulate cognitive deficits and neuropathology in 3xTg-AD mice.

Platelets: A new therapeutic target for neurological diseases.

Amyloid-beta (Aβ) plaques and the intracellular buildup of hyperphosphorylated tau protein are hallmarks of Alzheimer's disease (AD), a progressive neurodegenerative disease that causes synaptic dysfunction and neuronal death. Glycogen synthase kinase 3 beta (GSK3β), protein kinase B (AKT), and phosphatidylinositol 3-kinase all have aberrant signaling pathways that contribute to the pathophysiology of AD. The PI3K/AKT neuroprotective pathway is seriously inhibited in AD, which leads to brain insulin resistance (BIR) and neurodegeneration. However, AD leads to hyperactivation of GSK3β, which in turn produces tau hyperphosphorylation, Aβ accumulation, and cognitive impairment. BIR and PI3K/AKT/GSK3β signaling in AD have a complicated interaction that is covered in this article. The pathway has both neuroprotective and pathogenic functions. The therapeutic use of GSK3β inhibitors and PI3K/AKT activators to decrease AD pathogenesis is also discussed. Changing these pathways can improve cognitive function, reduce tau and Aβ pathology, and restore insulin signaling, according to preclinical and clinical research. Finding highly specialized treatments with minimal side effects remains a challenge. More research is required to thoroughly assess the safety and efficacy of medications that target specific pathways and to clarify the molecular mechanisms underlying PI3K/AKT/GSK3β dysregulation in AD in order to create novel and effective treatment alternatives.

Chronic cerebral ischemia is a significant contributor to cognitive impairment, which plays a crucial role in the pathogenesis of vascular dementia (VaD). While tau hyperphosphorylation is acknowledged as a critical risk factor, the precise mechanisms underlying this process remain poorly understood. Recent studies have indicated a significant correlation between low abundance of intestinal short-chain fatty acids (SCFAs) and tau hyperphosphorylation. In this study, we assessed neurological function in mice subjected to chronic cerebral ischemia through bilateral common carotid artery stenosis (BCAS) and in cells through oxygen-glucose deprivation (OGD). In our investigation, we observed cognitive deficits in chronic cerebral ischemia mice. This was accompanied by dysbiosis of the intestinal microbiota, markedly reduced levels of acetic acid (Ace), aberrant Erk activation, and increased tau hyperphosphorylation. Notably, supplementation with Ace exhibits a significant neuroprotective effect. Utilizing both BCAS mice and OGD cell models, our study elucidated that Ace can ameliorate cognitive impairment induced by chronic cerebral ischemia. The underlying mechanism may involve a reduction in tau hyperphosphorylation, potentially mediated through the inhibition of Erk activity via the free fatty acid receptor 3 (FFAR3)/Erk signaling pathway. This research provides novel insights into the pathophysiology of VaD resulting from chronic cerebral ischemia and offers potential therapeutic strategies for its clinical management, highlighting the significance of targeting metabolic dysregulation in the prevention and treatment of cognitive decline.

Tau is a microtubule-associated protein. Hyperphosphorylation of tau at neurotoxic sites, particularly at Thr231 within the Thr231-Pro motif, is a pathological hallmark of Alzheimer's disease (AD) and other tauopathies. Phosphorylated tau at Thr231 exists in two distinct conformations: cis and trans. The Cis pThr231-Pro Tau confomer is neurotoxic and promotes neurodegeneration. Furthermore, tau is subject to O-linked N-acetylglucosamine (O-GlcNAc) modification, and it has been suggested that O-GlcNAcylation of tau can influence tau phosphorylation. In this study, we utilized Thiamet G, an O-GlcNAcase (OGA) inhibitor, to elevate tau O-GlcNAcylation levels. Our findings demonstrate that treatment of nutrient-deprived primary cortical neurons with this OGA inhibitor increased tau O-GlcNAcylation, inhibited the formation of the neurotoxic Cis p-Tau conformation, and reduced neuronal cell loss. Additionally, we observed that the Trans p-Tau conformation represents a normal conformer under physiological conditions. Collectively, our data support tau O-GlcNAcylation as a promising therapeutic strategy for Alzheimer's disease and other tauopathies.

Triggering receptor expressed on myeloid cells 2 (TREM2) is an innate immune receptor abundantly expressed in microglia in the brain. Our previous study indicated that TREM2 promoted microglia polarization to the M2 phenotype in APP/PS1 transgenic mice and BV2 cells. It is reported that M2 microglia release brain-derived neurotrophic factor (BDNF) to enhance adult neurogenesis in the hippocampus. However, the role of TREM2 in hippocampal neurogenesis and the underlying mechanism are still less known. Apolipoprotein E knockout (ApoE-/-) mice exhibit cholinergic dysfunction, tau hyperphosphorylation, synaptic loss and dysfunction that may affect brain function and simulate Alzheimer's disease (AD). In this study, overexpression of TREM2 significantly increased the number of minichromosome maintenance 2 (MCM2) and doublecortin (DCX) cells in the subgranular zone (SGZ) of ApoE-/- mice. Additionally, the protein levels of MCM2 and DCX showed a similar trend. Furthermore, we found that overexpression of TREM2 promoted a phenotypical switch from M1 to M2 in microglia, as the levels of tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β), and CD86 were decreased, whereas the levels of IL-4, Arginase-1(Arg-1), BDNF, and CD206 were increased. Importantly, overexpression of TREM2 activated the phosphatidylinositol 3-kinase/protein kinase B (PI3K/Akt) and extracellular signal-regulated protein kinase 1 and 2 (ERK1/2) signaling pathways. In vitro, overexpression of TREM2 in primary microglia increased the production of anti-inflammatory factors (IL-4, Arg-1) and BDNF, while decreasing the production of pro-inflammatory factors (TNF-α, IL-1β). Furthermore, conditioned medium (CM) from TREM2 overexpressing primary microglia facilitated neural stem cells (NSCs) proliferation and differentiation into neurons. Moreover, the mechanistic study indicated that overexpression of TREM2 modulated microglial M2 polarization and promoted the proliferation and differentiation of NSCs partly via the PI3K/Akt and ERK1/2 signaling pathways. Collectively, these findings revealed that TREM2 may modulate microglial M2 polarization to inhibit neuroinflammation and increase the M2 microglia-derived BDNF to rescue hippocampal neurogenesis in ApoE-/- mice, and TREM2 can be considered a promising therapeutic factor to promote neurogenesis in AD and other brain diseases.

Alzheimer’s disease (AD) is the leading cause of dementia in elderly individuals worldwide; however, all mechanisms leading to disease onset and progression are not well understood. Here, we report brain single-cell multiome and spatial transcriptomics in a transgenic rat model of human-like tauopathy. We have identified new markers of tau-driven AD pathology and provided single-cell evidence for genes implicated in AD. Our findings reveal how tau hyperphosphorylation and aging alter ligand-receptor communication, transcription factor regulatory networks, and specific cellular networks. Notably, we found intriguing changes in cell communication involving glutamatergic transmission and Netrin signaling as a taupathy consequence. Overall, this study reinforces the concept that synaptic dysfunction is a critical early event in AD and highlights potential targets as potential therapeutic strategies.

Abstract The aim of this study was to investigate the protective effects of brown algae, namely Sargassum thunbergii (ST) and Sargassum fusiforme (SF), on memory and cognitive impairment, development of Alzheimer’s disease (AD), oxidative stress, and microglial activation in D-galactose (D-gal)-induced aging rats. Adult male Sprague Dawley rats were administered D-gal (150 mg/kg, i.p.) and a daily dose of hot water extract of ST (150 and 300 mg/kg) or SF (300 mg/kg) or phosphatidylserine [(PS) 30 mg/kg, positive control] for 13 weeks. ST, SF, and PS exhibited improved memory and cognition impairment in both radial arm maze and novel object recognition tests. Administration of ST, SF, and PS attenuated amyloid beta (Aβ) levels by decreasing Aβ production and increasing Aβ clearance-related proteins in the brains of D-gal-induced aging rats. However, only the ST group showed reduced expression of hyper-phosphorylated tau proteins in the brain by suppressing glycogen synthase kinase 3 beta (GSK3β) activities. Moreover, ST, SF, and PS also decreased acetylcholinesterase activity, oxidative stress, microglia activation, and inflammation, and increased the microglial M2 phenotype in the rat brain compared to D-gal-treated control rats. These results indicate that ST and SF could be potential candidates to ameliorate the risk of AD.

Tau hyperphosphorylation has been considered a major contributor to neurodegeneration in Alzheimer's disease (AD) and frontotemporal dementia, and related tauopathies have gained prominence in the development of therapies for these conditions. Glial responses are key features of AD and frontotemporal dementia, and are associated with neuroinflammation. Numerous transgenic mouse models that recapitulate critical AD-like pathology and cognitive impairment have been developed to examine pathogenic mechanisms and evaluate therapeutic approaches targeting tau and glial reactivity. Glial reactivity and neuroinflammation coincide with tau hyperphosphorylation, which induces behavioral impairment; however, the specific correlation between glial cell activation and abnormal behavior remains unknown. In this study, we investigated changes in glial cell gene expressions related to abnormal behaviors in rTg4510 mice, which phenocopy the tau pathology, neuroinflammation, and neurodegeneration observed in human tauopathies. Both 4- and 6-month-old rTg4510 mice displayed significantly impaired nest-building behavior compared with control mice. Paired association learning was also impaired in 4-month-old rTg4510 mice. Moreover, rTg4510 mice of both age groups exhibited abnormal exploratory behavior, and these mice spent a longer time in the open arms of the plus-maze test than control mice. Using a magnetic-activated cell-sorting technique, we analyzed glial cell gene expressions related to neuroinflammation, phagocytosis, and amyloid synthesis in the prefrontal cortex of rTg4510 mice. Regression analysis of glial gene expressions and behavioral tests revealed that various glial reactivities were associated with behavioral abnormalities. Our findings suggest specific genetic characteristics of glial cells that may lead to abnormal behavior in rTg4510 mice.

The convergence of peptides and nanoparticles through bionanoconjugation has emerged as a transformative strategy to address the persistent challenges in treating neurodegenerative disorders. Peptides, particularly short sequences (< 45 amino acids), offer unique advantages as protein mimetics, including structural flexibility, target specificity and blood-brain barrier permeability. Their clinical translation is hindered by rapid enzymatic degradation, short half-life, and poor bioavailability. Conjugation with nanoparticles, overcomes these limitations by enhancing stability, prolonging circulation, and enabling precise targeting. Peptide-nanoparticle conjugates, including TAT-functionalized gold nanoparticles and RGD-decorated polymeric systems, have shown significant improvements in blood brain barrier penetration. These advancements are associated with a reduction in amyloid-beta aggregation and the inhibition of tau hyperphosphorylation in preclinical models. These hybrids leverage peptides dual roles as therapeutic agents and drug carriers, often exploiting receptor-mediated transport for brain delivery. This review critically evaluates covalent and noncovalent conjugation strategies, such as carbodiimide chemistry, ligand exchange, and click reactions, highlighting their impact on structural stability and bioactivity. We further discuss advances in peptide classes, including cell-penetrating peptides, nuclear localization signals, targeting peptides and bioactive peptides, emphasizing their applications in mitigating oxidative stress, neuroinflammation, and protein misfolding in neurodegenerative disorders. Despite promising preclinical outcomes, challenges such as scalability, immunogenicity, and heterogeneous blood brain barrier models remain barriers to clinical translation. This review outlines a strategy for enhancing peptide-NP conjugates as future neurotherapeutics by integrating existing methodologies, therapeutic results, and challenges. This underscores the importance of collaborative efforts across various disciplines to bridge the gap between advancements in nanotechnology and their clinical applications.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by dementia and inexorable loss of neurons. Despite extensive research, the currently approved drugs offer only limited efficacy which highlights the need for exploring novel synergistic natural compounds capable of mitigating multiple targets of AD. This study evaluated the neuroprotective potential of the synergistic combination of Vitexin and Thymol using computational and in vitro model systems in N2a cells. Computational pharmacokinetic screening revealed the blood-brain barrier (BBB) permeability of thymol and 0.55 bioavailability score for Vitexin. Molecular docking studies showed higher binding affinity of Vitexin with JNK and Thymol with COX-1 and CAMK-II and 100 ns molecular dynamics simulation exhibited stable binding with sustained hydrogen bond and hydrophobic interactions. Based on the IC50 values [Vitexin (135.24µg/ml, 312.9 µM) and Thymol (36.91µg/ml, 245.7 µM)] and combination index (CI < 1) determined by the acetylcholinesterase (AChE) inhibition assay and checkerboard assay (performed with 15 different combinations) respectively, the effective combination (Vitexin 45.08µg/ml; Thymol 7.382µg/ml; CI = 0.53) was fixed for further studies. In okadaic acid (OA) induced neurotoxicity model, pre-treatment with the combination significantly increased the cell viability (88.36 ± 3.73%) (n = 3). Real-time PCR results revealed the upregulation of PP1 gene expression and modulation of MAPK family (MEK1/2, ERK1/2 and JNK), and other tau related kinases (GSK3β, CAMKII and P70 s6). The above findings demonstrate that the combination of Vitexin and Thymol effectively protect the neuronal cells from OA induced cytotoxicity and modulate the hyperactivation of kinases, suggesting its potential in preventing tau hyperphosphorylation in AD conditions.

The retrosplenial cortex (RSC) is a critical brain region that is activated during spatial memory tasks and plays a crucial role in the consolidation of long-term memory. Various classes of RSC excitatory neurons across different laminar layers serve as the central hub for neuronal connections between the RSC and other brain regions, such as the hippocampus. Despite the established role of the RSC in spatial memory, the transcriptomic signature of the neuronal subtypes in the RSC during spatial memory consolidation remained elusive. Here, we used unbiased and targeted spatial transcriptomics to identify the RSC transcriptional signature after a spatial memory task. Genes related to transcription regulation, protein folding, and mitogen-activated protein kinase pathways were upregulated in the RSC during an early time window of memory consolidation. Furthermore, cell-type and excitatory neuronal layer-specific changes in gene expression were resolved using Xenium spatial transcriptomics. A deep learning computational tool uncovered cell-type-specific molecular activation patterns within the RSC after learning. Conversely, in a mouse model of Alzheimer's disease and related dementia (ADRD) exhibiting tau hyperphosphorylation in the RSC, there was a reduction in predicted neuronal activation following learning. Notably, learning-induced Fos expression was decreased in excitatory neurons of the RSC in the ADRD mice. Finally, we observed that blocking RSC excitatory neurons during the early temporal window after learning using a chemogenetic approach impaired long-term spatial memory in adult mice. Our results reveal a molecular signature of the RSC after learning and emphasize the role of RSC excitatory neurons during spatial memory consolidation.

Prion diseases and Alzheimer’s disease share many similarities in seeding activity, symptomatic and pathological presentations, and mechanisms of neurodegeneration. Accordingly, it is pertinent to inquire whether Alzheimer’s should be considered; and therefore treated like; a prion disease. This mental framework would likely guide many to target the seeding of Alzheimer’s as a method for altering disease progression. This review cross examines both diseases to dissect the limits to their overlap and understand how these similarities can be exploited for more effective treatment. While conventional wisdom has chosen to focus on the common seeding properties in each disease, this review concludes that targeting seeding in Alzheimer’s disease would not be as effective in treating it; as opposed to targeting seeding in prion diseases. Seeding in prion diseases drives conversion from the antiapoptotic cellular Prion Protein (PrPc) to toxic scrapie Prion Protein (PrPsc). While seeding of amyloid-β in Alzheimer’s does not drive such analogous conversion of benign monomers to a toxic state. The seeding activity of hyperphosphorylated tau (HPT) in Alzheimer’s does. This implies promise for using anti-aggregation therapies effective for PrPsc in taupathies, on HPT in Alzheimer’s. However, given that this event is downstream of amyloid-β seeding and that tau can become toxic through other means, even modulating HPT seeding may not be as effective a therapeutic target in Alzheimer’s, as it may be in prion diseases. The intracellular interactions of amyloid-β and HPT exploit similar pathways in triggering apoptosis as in PrPsc. Thus, therapeutics that target these common pathways would be effective in both diseases. Additionally, while PrPc has been shown to contribute to amyloid-β toxicity, this review suggests that blocking the binding between the two proteins via allosteric or competitive inhibitors, rather than completely eradicating PrPc, would be the most optimal treatment. Such a therapy could also be applied to PrPc/PrPsc binding in prion diseases. Such a change in the thinking framework could significantly increase druggable targets for both prion and Alzheimer’s therapeutics. This could also expand the relevancy of niche fields of study, like mitochondrial dynamics, from application to a singular disease, to multiple diseases.

Near-infrared light-triggered methylene blue/berberine co-loaded polydopamine nanoparticles modified with sialic acid for Alzheimer's disease therapy.

Reduced binding of Tau(210-240) to BIN1: Phosphate charges prefer n-Src/distal loops over RT-Src loops.

Neuroinflammatory suppression with protocatechuic acid attenuates Alzheimer's disease phenotypes in 5 ×FAD transgenic mice.