Sporadic Form Of Alzheimer's Disease Research Articles

INPP5D/SHIP1: Expression, Regulation and Roles in Alzheimer's Disease Pathophysiology.

Alzheimer's disease (AD) is the most common form of dementia, accounting for approximately 38.5 million cases of all-cause dementia. Over 60% of these individuals live in low- and middle-income countries and are the worst affected, especially by its deleterious effects on the productivity of both patients and caregivers. Numerous risk factors for the disease have been identified and our understanding of gene-environment interactions have shed light on several gene variants that contribute to the most common, sporadic form of AD. Microglial cells, the innate immune cells of the central nervous system (CNS), have long been established as guardians of the brain by providing neuroprotection and maintaining cellular homeostasis. A protein with a myriad of effects on various important signaling pathways that is expressed in microglia is the Src Homology 2 (SH2) domain-containing Inositol 5' Phosphatase 1 (SHIP1) protein. Encoded by the INPP5D (Inositol Polyphosphate-5-Phosphatase D) gene, SHIP1 has diminutive effects on most microglia signaling processes. Polymorphisms of the INPP5D gene have been found to be associated with a significantly increased risk of AD. Several studies have elucidated mechanistic processes by which SHIP1 exerts its perturbations on signaling processes in peripheral immune cells. However, current knowledge of the controllers of INPP5D/SHIP1 expression and the idiosyncrasies of its influences on signaling processes in microglia and their relevance to AD pathophysiology is limited. In this review, we summarize these discoveries and discuss the potential of leveraging INPP5D/SHIP1 as a therapeutic target for Alzheimer's disease.

Differential impact of APOE genetic variants on autosomal dominant‐ and sporadic‐ Alzheimer disease

AbstractBackgroundVariants in the apolipoprotein E (APOE) gene represent the greatest genetic risk factor for Alzheimer disease (AD). Carriers of the ε4 allele have an increased risk of developing AD pathology and a lower age of symptom onset. While prior work has focused on the sporadic form of AD, little is known about how the ε4 allele impacts AD‐specific pathology in autosomal dominant AD (ADAD).Method430 participants from the Charles and Joanne F. Knight Alzheimer Disease Research Center and 276 ADAD mutation‐carriers from the Dominantly Inherited Alzheimer Network, were included in these analyses. Participants were classified as ε4‐positive or ‐negative, and further grouped using Clinical Dementia Rating® (CDR®) scores as cognitively impaired or –unimpaired (Table 1). All participants completed magnetic resonance imaging (MRI), beta‐amyloid positron emission tomography (Ab‐PET), and cognitive testing within a 12‐month period.ResultUsing regression models, we replicated prior work demonstrating that the ε4 allele is associated with an increase in AD pathology measured by Ab‐PET and MRI in a sporadic AD cohort. Furthermore, the ε4 allele was also associated with a decline in cognitive performance. Follow‐up pairwise comparisons revealed that within the sporadic‐AD cohort, the influence of the ε4 allele was most pronounced in individuals who were cognitively impaired. In contrast, in a cohort of individuals possessing autosomal dominant mutations, the ε4 allele was not associated with increases in pathology measured by Ab‐PET and MRI, nor was it associated with a decrease in cognition (Table 1; Figure 1).ConclusionWe present quantitative evidence that the APOE‐ ε4 allele differentially impacts the pathology and cognitive outcomes of sporadic‐ and autosomal dominant AD. In those with sporadic AD, possession of at least one copy of the ε4 allele is associated with increased amyloid deposition and cortical thinning, as well as decreased cognition, particularly in individuals who are cognitively impaired. However, in ADAD mutation‐carriers, these same patterns are not evident. We propose that this is due to the overwhelming influence of the autosomal dominant genetic mutations that drive this unique and rare form of AD.

Amyloid-β removal from the brain is blocked by circulating amyloid-forming amylin secreted by the pancreas.

Increasing amyloid-β (Aβ) transport from the brain provides a novel therapeutic approach for Alzheimer's disease (AD). Our team recently showed: 1, the brain microvasculature accumulates amylin, an amyloid-forming hormone secreted from the pancreas, in both familial and sporadic forms of AD; 2, amylin and Aβ often co-localize in the brain parenchyma and microvasculature; 3, cerebrovascular amylin deposition is associated with behavioral deficits in rats, independent of Aβ pathology; and 4, pancreatic expression of human amylin in APPswe/PS1dE9 (APP/PS1) rats accelerates the development of AD-like pathology. We tested the hypothesis that the removal of Aβ from the brain is in part affected by amylin deposition in the brain microvasculature. Amylin levels were measured in blood from 38 cognitively impaired and 41 cognitively unimpaired individuals. Evidence of amylin-Aβ co-localization was assessed in brain slices from 56 persons with AD and 37 cognitively unaffected individuals. To explore the potential mechanisms by which amylin might affect Aβ transport, we genetically manipulated amylin secretion in APP/PS1 and non-APP/PS1 rats. Average blood amylin levels were higher in those with dementia (DEM) or mild cognitive impairment (MCI) compared to those who were cognitively unimpaired (CU) (8.0 ± 2.2 pM vs. 4.7 ± 1.4 pM vs. 2.8 ± 0.5 pM; one-way ANOVA, P < 0.0001). In human AD brains and brains of APP/PS1 rats with pancreatic expression of amyloid-forming human amylin, Aβ accumulation within the perivascular space frequently co-localized with amylin deposits. In non-APP/PS1 rats expressing human amylin, amylin accumulated in brain capillaries which induced downregulation of the low-density lipoprotein receptor-related protein 1 (LRP1), the Aβ transport protein, and was associated with a lower plasma-to-brain Aβ ratio compared to wild type littermates (0.52 ± 0.01 vs. 0.64 ± 0.02, P = 0.0021). Systemic amylin dyshomeostasis leads to amylin accumulation in small cerebral vessels causing cerebral microvascular dysfunction and interference with vascular routes for Aβ removal from the brain. Lowering the blood amylin level in early AD could improve Aβ clearance from the brain.

Crocin mitigated cognitive impairment and brain molecular alterations induced by different intensities of prenatal hypoxia in neonatal rats.

IntroductionBrain hypoxia has important role to the onset and progression of sporadic form of Alzheimer disease via expression of hypoxia‐inducible factor‐1 (HIF‐1). Crocin by anti‐amyloidogenic property inhibits β‐amyloid formation. However, the molecular mechanism associated with anti‐amyloidogenic activity of crocin is unknown. So, the present study was designed to investigate the effect of crocin on cognitive behavior and expression of HIF‐1α and β‐secretase (BACE1) genes in the brain of neonate rats following different intensities of hypoxia during pregnancy.Material and methodsPregnant female rats were divided into six groups including sham, control crocin treated (CC), hypoxia with three different intensities (H1–H3), and most intense of hypoxic group treated with crocin (H3C) (30 mg/kg; i.p) at P14. Hypoxia induced on the 20th day of pregnancy. Animals in sham and CC were put in hypoxia chamber at the same time of hypoxia group without any hypoxia induction. Morris water maze (MWM) and qRT‐PCR were used to evaluate the cognitive behavior and mRNA levels of BACE1 and HIF‐1α genes in the brain tissues.ResultsAnimal under 7% O2 + 93% N2 condition for 3 hr showed the highest cognitive behavior impairment and upregulated HIF‐1α and BACE1 mRNA in brains of offspring (p < .001). Crocin treatment improved memory impairment and attenuated the gene expression of HIF‐1α and BACE1 in the brains of neonate rat.ConclusionsIt was concluded that crocin has beneficial effects on the brain of neonate rats under gestational hypoxia by improvement of memory impairment and molecular alteration related to hypoxia.

Sorting Out the Role of the Sortilin-Related Receptor 1 in Alzheimer's Disease.

Sortilin-related receptor 1 (SORL1) encodes a large, multi-domain containing, membrane-bound receptor involved in endosomal sorting of proteins between the trans-Golgi network, endosomes and the plasma membrane. It is genetically associated with Alzheimer’s disease (AD), the most common form of dementia. SORL1 is a unique gene in AD, as it appears to show strong associations with the common, late-onset, sporadic form of AD and the rare, early-onset familial form of AD. Here, we review the genetics of SORL1 in AD and discuss potential roles it could play in AD pathogenesis.

Unravelling Alzheimer's Disease: It's Not the Whole Story, but Aβ Still Matters.

In late 2016, we solicited a series of reviews covering the variety of processes that appeared to be involved in the pathogenesis of neurodegenerative disorders, particularly Alzheimer's disease (AD). These essays have appeared at regular intervals in The FASEB Journal. My instructions to the researchers were simply not to emphasize Aβ per se because there had been many reviews both supporting and questioning the etiologic role of Aβ in the late-onset, sporadic form of AD, and reciting either of those scientific positions would be redundant. My colleagues responded admirably, and I believe that their contributions have significantly informed readers' awareness of the current state of knowledge of AD. I have written my epilogue from the perspective of an investigator interested in the role of protein aggregation in human disease and as a physician who may be charged with making a diagnosis and prescribing treatment for a patient. We do not yet have etiology-based therapies of AD, but we continue to gain insight into the mechanisms responsible for synaptic loss and the consequent functional deterioration. A silver therapeutic bullet does not seem to be in the offing. It is more likely that an iterative approach will lead to the development of a group of treatments that are AD specific or applicable to various features of the entire class of neurodegenerative disorders. How and when those therapies succeed or fail will, in turn, provide additional insights into disease pathogenesis, which will inform the development of succeeding generations of therapeutics.-Buxbaum, J. N. Unravelling Alzheimer's disease: it's not the whole story, but Aβ still matters.

Therapeutic targeting of nuclear receptors, liver X and retinoid X receptors, for Alzheimer's disease.

After 15years of research into Alzheimer's disease (AD) therapeutics, including billions of US dollars provided by federal agencies, pharmaceutical companies, and private foundations, there are still no meaningful therapies that can delay the onset or slow the progression of AD. An understanding of the proteolytic processing of amyloid precursor protein (APP) and the hypothesis that pathogenic mechanisms in familial and sporadic forms of AD are very similar led to the assumption that pharmacological inhibition of secretases or immunological approaches to clear amyloid depositions in the brain would have been the core to drug discovery strategies and successful therapies. However, there are other understudied approaches including targeting genes, gene networks, and metabolic pathways outside the proteolytic processing of APP. The advancement of newly developed sequencing technologies and mass spectrometry, as well as the availability of animal models expressing human apolipoprotein E isoforms, has been critical in rationalizing additional AD therapeutics. The purpose of this review is to present one of those approaches, based on the role of ligand-activated nuclear liver X and retinoid X receptors in the brain. This therapeutic approach was initially proposed utilizing in vitro models 15years ago and has since been examined in numerous studies using AD-like mouse models. LINKED ARTICLES: This article is part of a themed section on Therapeutics for Dementia and Alzheimer's Disease: New Directions for Precision Medicine. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.18/issuetoc.

The vexing complexity of the amyloidogenic pathway.

The role of the amyloidogenic pathway in the etiology of Alzheimer's disease (AD), particularly the common sporadic late onset forms of the disease, is controversial. To some degree, this is a consequence of the failure of drug and therapeutic antibody trials based either on targeting the proteases in this pathway or its amyloid end products. Here, we explore the formidable complexity of the biochemistry and cell biology associated with this pathway. For example, we review evidence that the immediate precursor of amyloid-β, the C99 domain of the amyloid precursor protein (APP), may itself be toxic. We also review important new results that appear to finally establish a direct genetic link between mutations in APP and the sporadic forms of AD. Based on the complexity of amyloidogenesis, it seems possible that a major contributor to the failure of related drug trials is that we have an incomplete understanding of this pathway and how it is linked to Alzheimer's pathogenesis. If so, this highlights a need for further characterization of this pathway, not its abandonment.

Posterior Cortical Atrophy.

This article presents an overview of the clinical syndrome of posterior cortical atrophy (PCA), including its pathologic underpinnings, clinical presentation, investigation findings, diagnostic criteria, and management. PCA is usually an atypical form of Alzheimer disease with relatively young age at onset. New diagnostic criteria allow patients to be diagnosed on a syndromic basis as having a primary visual (pure) form or more complex (plus) form of PCA and, when possible, on a disease-specific basis using biomarkers or underlying pathology. Imaging techniques have demonstrated that some pathologic processes are concordant (atrophy, hypometabolism, tau deposition) with clinical symptoms and some are discordant (widespread amyloid deposition). International efforts are under way to establish the genetic underpinnings of this typically sporadic form of Alzheimer disease. In the absence of specific disease-modifying therapies, a number of practical suggestions can be offered to patients and their families to facilitate reading and activities of daily living, promote independence, and improve quality of life SUMMARY: While rare, PCA is an important diagnostic entity for neurologists, ophthalmologists, and optometrists to recognize to allow for early accurate diagnosis and appropriate patient management. PCA provides an important opportunity to investigate the causes of selective vulnerability in Alzheimer disease.

Intracerebral Injection of Streptozotocin to Model Alzheimer Disease in Rats.

Animal models have promoted meaningful contribution to science including Alzheimer's disease (AD) research. Several animal models for AD have been used, most of them related to genetic mutations observed in familial AD. However, sporadic form of AD, also named late-onset is the most frequent form of the disease, which is multifactorial, being influenced by genetic, environmental and lifestyle factors. Here, we describe a protocol of an AD-like pathology of the sporadic form using Wistar rats by a single bilateral intracerebroventricular (icv) injection of streptozotocin (STZ, 2 mg/kg). Icv injection of STZ induces brain resistance to insulin and other pathological alterations related to those observed in AD, such as cognitive impairment and accumulation of phosphorylated tau protein and β-amyloid in the brain. Thus, icv injection of STZ is a useful tool to investigate the pathological mechanisms and the metabolic alterations involved in AD and to propose new therapeutic approaches and neuroprotective drugs.

Role of presynaptic calcium stores for neural network dysfunction in Alzheimer's disease.

Role of presynaptic calcium stores for neural network dysfunction in Alzheimer's disease.

Drugs Induced Alzheimer’s Disease in Animal Model

Alzheimer’s disease (AD) can be described by characteristics like dementia, mental and cognitive dysfunctions, and memory impairment. Nowadays, with progresses of science, attempts to treat many diseases have increased. Laboratory animals help to discover new ways of treating disease. AD induced by chemical drugs in animal models can be useful in better understanding the mechanisms of disease and treatment of AD. In recent decades, many researchers have reported transgenic rat models of AD but this modeling has a great problem and does not contain all kinds of AD. There are two types of AD, including familial (5% of all AD) and sporadic, but the transgenic model does not show the complete model of AD, especially in sporadic form of AD, which is 95% of AD cases. We decided to describe another modeling of AD using chemical drugs such as colchicine, scopolamine, okadaic acid, streptozotocin, and trimethyltin.[GMJ.2017;6(3):185-196] DOI:10.22086/gmj.v6i3.820

THE INFLUENCE OF LOW-DENSITY LIPOPROTEINS ON NEOCORTICAL AMYLOID LOAD IN THE AUSTRALIAN IMAGING BIOMARKER AND LIFESTYLE STUDY

In the last decade, attention has turned to the possible link between lipid metabolism and Alzheimer's disease (AD). Previous work using animals highlighted the need for further investigation into the mechanisms for AD pathogenesis. Recently, metabolic syndrome has been considered a risk factor for AD. This cluster of disorders, each with their own associated risk for AD, includes abnormal lipid and cholesterol metabolism as one of its core components. Cholesterol is considered to be important in sporadic forms of AD. A large proportion of cholesterol traffic is carried in the plasma as low density lipoprotein (LDL), which is usually rapidly cleared by the liver. It is also thought to have roles in the synthesis and clearance of amyloid-beta (Aβ). However, the actual mechanism in AD pathogenesis is poorly understood. In this cross-sectional comparison, we examined the plasma LDL lipoprotein profiles of clinically classified healthy control and Alzheimer's affected individuals from the Australian Imaging, Biomarker and Lifestyle (AIBL) study. These individuals had also undergone several other characterisations including PiB-PET imaging for determination of brain amyloid load. The data indicate that the APOE ε4 participants tended to have higher median levels of larger plasma LDL species while also being associated with higher amyloid load. These individuals also showed high variations in large LDL levels, indicating altered regulation of LDL metabolism. We also identified a possible association with LDL levels in non-ε4 participants and neocortical amyloid load, suggesting that plasma LDL is involved with AD pathogenesis. APOE ε4 influences the levels of plasma LDL species and is associated with higher amyloid load in the brain. The larger LDL species show positive association with higher brain amyloid load, supporting a metabolic link between brain and periphery.

Inhibition of Early Growth Response 1 in the Hippocampus Alleviates Neuropathology and Improves Cognition in an Alzheimer Model with Plaques and Tangles

A sporadic form of Alzheimer disease (AD) and vascular dementia share many risk factors, and their pathogenic mechanisms are suggested to be related. Transcription factor early growth response 1 (Egr-1) regulates various vascular pathologies and is up-regulated in both AD brains and AD mouse models; however, its role in AD pathogenesis is unclear. Herein, we report that silencing of Egr-1 in the hippocampus by shRNA reduces tau phosphorylation, lowers amyloid-β (Aβ) pathology, and improves cognition in the 3xTg-AD mouse model. Egr-1 silencing does not affect levels of cyclin-dependent protein kinase 5 (Cdk5), glycogen synthase kinase 3β, protein phosphatase 1, or protein phosphatase 2A, but reduces p35 subunit of Cdk5. Egr-1 silencing also reduces levels of β-secretase 1 (BACE-1) and BACE-1-cleaved amyloid precursor protein (APP) metabolites (secreted APPβ, C99, Aβ40, and Aβ42) but has no effect on presenilin 1 and presenilin 2. In hippocampal primary neurons, Egr-1 binds to BACE-1 and p35 promoters, enhances tau phosphorylation, activates Cdk5 and BACE-1, and accelerates amyloidogenic APP processing. Blocking Cdk5 action blocks Egr-1-induced tau phosphorylation but has no effect on BACE-1 activation and amyloidogenic APP processing. Blocking BACE-1 action, on the other hand, blocks Egr-1-induced amyloidogenic APP processing but does not affect tau phosphorylation. Egr-1 regulates tau phosphorylation and Aβ synthesis in the brain by respectively controlling activities of Cdk5 and BACE-1, suggesting that Egr-1 is a potential therapeutic candidate for the treatment of AD.

Aberrant iPSC-derived human astrocytes in Alzheimer's disease

The pathological potential of human astroglia in Alzheimer's disease (AD) was analysed in vitro using induced pluripotent stem cell (iPSC) technology. Here, we report development of a human iPSC-derived astrocyte model created from healthy individuals and patients with either early-onset familial AD (FAD) or the late-onset sporadic form of AD (SAD). Our chemically defined and highly efficient model provides >95% homogeneous populations of human astrocytes within 30 days of differentiation from cortical neural progenitor cells (NPCs). All astrocytes expressed functional markers including glial fibrillary acidic protein (GFAP), excitatory amino acid transporter-1 (EAAT1), S100B and glutamine synthetase (GS) comparable to that of adult astrocytes in vivo. However, induced astrocytes derived from both SAD and FAD patients exhibit a pronounced pathological phenotype, with a significantly less complex morphological appearance, overall atrophic profiles and abnormal localisation of key functional astroglial markers. Furthermore, NPCs derived from identical patients did not show any differences, therefore, validating that remodelled astroglia are not as a result of defective neural intermediates. This work not only presents a novel model to study the mechanisms of human astrocytes in vitro, but also provides an ideal platform for further interrogation of early astroglial cell autonomous events in AD and the possibility of identification of novel therapeutic targets for the treatment of AD.

The effects of different familial Alzheimer\u2019s disease mutations on APP processing in vivo

BackgroundDisturbed amyloid precursor protein (APP) processing is considered to be central to the pathogenesis of Alzheimer’s disease (AD). The autosomal dominant form of the disease, familial AD (FAD), may serve as a model for the sporadic form of AD. In FAD the diagnosis of AD is reliable and presymptomatic individuals carrying FAD mutations can give valuable insights into the earliest stages of the disease where therapeutic interventions are thought to be the most effective.MethodsIn the current cross-sectional study, products of APP processing (e.g., sAPPα, sAPPβ, Aβ38, Aβ40 and Aβ42) were measured in the cerebrospinal fluid (CSF) of individuals carrying one of three FAD mutations, APPswe (p.KM670/671NL), APParc (p.E693G) and PSEN1 (p.H163Y), as well as in non-mutation carriers from the same families.ResultsWe observed pathological APP processing in presymptomatic carriers of FAD mutations, with different profiles of APP and Aβ isoforms in the three mutation carrier groups, APPswe (p.KM670/671NL), APParc (p.E693G) and PSEN1 (p.H163Y), except for the well-established decrease in CSF Aβ42 that was found with all mutations.ConclusionsThese findings add to the current evidence that AD pathophysiology differs between disease-causing mutations and can be monitored in the presymptomatic disease stage by CSF analyses. This may also be important from a therapeutic standpoint, by opening a window to monitor effects of disease-modifying drugs on AD pathophysiology.

Alzheimer's Disease and Histone Code Alterations.

Substantial progress has been made in identifying Alzheimer's disease (AD) risk-associated variants using genome-wide association studies (GWAS). The majority of these risk variants reside in noncoding regions of the genome making their functional evaluation difficult; however, they also infer the presence of unconventional regulatory regions that may reside at these locations. We know from these studies that rare familial cases of AD account for less than 5% of all AD cases and autosomal dominant mutations in APP, PSEN1 and PSEN2 account for less than 10% of the genetic basis of these familial cases [1]. The sporadic form of AD, while more complex, still has a substantial genetic component evidenced by observational studies where 30-48% of AD patients have a first degree relative who is also affected [2]. In addition, the strongest risk factor after age is the APOE E4 polymorphism, and more than 20 other risk variants have been identified to date, reviewed in two recent papers [3, 4]. Monozygotic twin studies have revealed a discordance for AD, implicating that a combination of epigenetic and genetic factors are likely involved in the development of AD [5].

Evidence For and Against a Pathogenic Role of Reduced γ-Secretase Activity in Familial Alzheimer's Disease.

The majority of mutations causing familial Alzheimer's disease (fAD) have been found in the gene PRESENILIN1 (PSEN1) with additional mutations in the related gene PRESENILIN2 (PSEN2). The best characterized function of PRESENILIN (PSEN) proteins is in γ-secretase enzyme activity. One substrate of γ-secretase is encoded by the gene AMYLOID BETA A4 PRECURSOR PROTEIN (AβPP/APP) that is a fAD mutation locus. AβPP is the source of the amyloid-β (Aβ) peptide enriched in the brains of people with fAD or the more common, late onset, sporadic form of AD, sAD. These observations have resulted in a focus on γ-secretase activity and Aβ as we attempt to understand the molecular basis of AD pathology. In this paper we briefly review some of the history of research on γ-secretase in AD. We then discuss the main ideas regarding the role of γ-secretase and the PSEN genes in this disease. We examine the significance of the "fAD mutation reading frame preservation rule" that applies to PSEN1 and PSEN2 (and AβPP) and look at alternative roles for AβPP and Aβ in fAD. We present a case for an alternative interpretation of published data on the role of γ-secretase activity and fAD-associated mutations in AD pathology. Evidence supports a "PSEN holoprotein multimer hypothesis" where PSEN fAD mutations generate mutant PSEN holoproteins that multimerize with wild type holoprotein and dominantly interfere with an AD-critical function(s) such as autophagy or secretion of Aβ. Holoprotein multimerization may be required for the endoproteolysis that activates PSENs' γ-secretase activity.

Epigenetic Regulation in Amyloid Precursor Protein with Genomic Rearrangements and the Lesch-Nyhan Syndrome

Recently, epigenetic regulation of alternative APP pre-mRNA splicing in the Lesch-Nyhan syndrome (LNS) has been studied (see Ref. 7) and showed for the first time, the presence of several APP-mRNA isoforms encoding divers APP protein isoforms ranging from 120 to 770 amino acids (with or without mutations and/or deletions). Here, by continuing on this work, I identified, for the first time new APP-mRNA isoforms with a deletion followed by an insertion (INDELS) in LNS and LNVs patients:c.19_2295delinsG166TT…GAGTCC…CTTAGTC…TCT489,p.Leu7Valfs*2;c.19_2295 delinsG169TT…GAGACC…CTTGGTC…TCT492,p.Leu7Valfs*2;and c.16_2313delinsG84CC…CAT616,p.Leu7Hisfs*45. A role of genomic rearrangements of APP gene via the Fork Stalling and Template Switching (FoSTeS) mechanism leading to INDELS was suggested. Epistasis between mutated HPRT1 and APP genes could be one of the factors of epigenetic modifications responsible for genomic rearrangements of APP gene. My findings accounted for epigenetic mechanism in the regulation of alternative APP pre-mRNA splicing as well as for epigenetic control of genomic rearrangements of APP gene may provide therefore new directions not only for investigating the role of APP in neuropathology associated with HGprt-deficiency in LNS and LNVs patients but also for the research in neurodevelopmental and neurodegenerative disorders by which APP gene involved in the pathogenesis of the diseases such as autism, fragile X syndrome (FXS), and Alzheimer's disease (AD) with its diversity and complexity, especially for sporadic form of AD (SAD). An accurate quantification of various APP-mRNA isoforms in brain tissues for detection of initial pathological changes or pathology development is needed and antisense drugs are the potential treatments.

Autophagy is involved in oral rAAV/Aβ vaccine-induced Aβ clearance in APP/PS1 transgenic mice.

The imbalance between ß-amyloid (Aß) generation and clearance plays a fundamental role in the pathogenesis of Alzheimer's disease (AD). The sporadic form of AD is characterized by an overall impairment in Aß clearance. Immunotherapy targeting Aß clearance is believed to be a promising approach and is under active clinical investigation. Autophagy is a conserved pathway for degrading abnormal protein aggregates and is crucial for Aß clearance. We previously reported that oral vaccination with a recombinant AAV/Aß vaccine increased the clearance of Aß from the brain and improved cognitive ability in AD animal models, while the underlying mechanisms were not well understood. In this study, we first demonstrated that oral vaccination with rAAV/Aß decreased the p62 level and up-regulated the LC3B-II/LC3B-I ratio in APP/PS1 mouse brain, suggesting enhanced autophagy. Further, inhibition of the Akt/mTOR pathway may account for autophagy enhancement. We also found increased anti-Aß antibodies in the sera of APP/PS1 mice with oral vaccination, accompanied by elevation of complement factors C1q and C3 levels in the brain. Our results indicate that autophagy is closely involved in oral vaccination-induced Aß clearance, and modulating the autophagy pathway may be an important strategy for AD prevention and intervention.