PTPRS is a novel marker for early Tau pathology and synaptic integrity in Alzheimer's disease.

We examined the role of protein tyrosine phosphatase receptor sigma (PTPRS) in the context of Alzheimer's disease and synaptic integrity. Publicly available datasets (BRAINEAC, ROSMAP, ADC1) and a cohort of asymptomatic but "at risk" individuals (PREVENT-AD) were used to explore the relationship between PTPRS and various Alzheimer's disease biomarkers. We identified that PTPRS rs10415488 variant C shows features of neuroprotection against early Tau pathology and synaptic degeneration in Alzheimer's disease. This single nucleotide polymorphism correlated with higher PTPRS transcript abundance and lower p(181)Tau and GAP-43 levels in the CSF. In the brain, PTPRS protein abundance was significantly correlated with the quantity of two markers of synaptic integrity: SNAP25 and SYT-1. We also found the presence of sexual dimorphism for PTPRS, with higher CSF concentrations in males than females. Male carriers for variant C were found to have a 10-month delay in the onset of AD. We thus conclude that PTPRS acts as a neuroprotective receptor in Alzheimer's disease. Its protective effect is most important in males, in whom it postpones the age of onset of the disease.

PTPRS is a novel marker for early tau pathology and synaptic integrity in Alzheimer's disease.

We examined the role of protein tyrosine phosphatase receptor sigma (PTPRS) in the context of Alzheimer's disease and synaptic integrity. Publicly available datasets (BRAINEAC, ROSMAP, ADC1) and a cohort of asymptomatic but "at risk" individuals (PREVENT-AD) were used to explore the relationship between PTPRS and various Alzheimer's disease biomarkers. We identified that PTPRS rs10415488 variant C shows features of neuroprotection against early tau pathology and synaptic degeneration in Alzheimer's disease. This single nucleotide polymorphism correlated with higher PTPRS transcript abundance and lower P-tau181 and GAP-43 levels in the CSF. In the brain, PTPRS protein abundance was significantly correlated with the quantity of two markers of synaptic integrity: SNAP25 and SYT-1. We also found the presence of sexual dimorphism for PTPRS, with higher CSF concentrations in males than females. Male carriers for variant C were found to have a 10-month delay in the onset of AD. We thus conclude that PTPRS acts as a neuroprotective receptor in Alzheimer's disease. Its protective effect is most important in males, in whom it postpones the age of onset of the disease.

MSR1 and NEP Are Correlated with Alzheimer's Disease Amyloid Pathology and Apolipoprotein Alterations.

BACKGROUND: In mouse models of amyloidosis, macrophage receptor 1 (MSR1) and neprilysin (NEP) have been shown to interact to reduce amyloid burden in the brain. OBJECTIVE: The purpose of this study is to analyze these two gene products in combination with apolipoproteins and Aß1-42 in the cerebrospinal fluid (CSF) and plasma of individuals at different stages of Alzheimer's disease (AD), as well as in autopsied brain samples from ROSMAP (Religious Orders Study and Memory and Aging Project). METHODS: CSF/plasma levels of MSR1 and NEP were measured using the sensitive primer extension assay technology. CSF Aß1-42 was assessed with ELISA, while CSF ApoE and ApoJ were measured with the Luminex's multiplex technology. Brain MSR1, APOE, and CLU (APOJ) mRNA levels were measured with RNA-Seq and contrasted to amyloid plaques pathology using CERAD staging. RESULTS: While plasma and CSF MSR1 levels are significantly correlated, this correlation was not observed for NEP. In addition to be highly correlated to one another, CSF levels of both MSR1 and NEP are strongly correlated with AD status and CSF Aß1-42, ApoE, and ApoJ levels. In the cortical tissues of subjects from ROSMAP, MSR1 mRNA levels are correlated with CLU mRNA levels and the CERAD scores but not with APOE mRNA levels. CONCLUSION: The discrepancies observed between CSF/plasma levels of MSR1 and NEP with CSF Aß1-42 and ApoE concentrations can be explained by many factors, such as the disease stage or the involvement of the blood-brain barrier breakdown that leads to the infiltration of peripheral monocytes or macrophages.

Apolipoprotein B is a novel marker for early tau pathology in Alzheimer's disease.

INTRODUCTION: We examine the role of brain apolipoprotein B (apoB) as a putative marker of early tau pathology and cognitive decline. METHODS: Cerebrospinal fluid (CSF) samples from cognitively normal and Alzheimer's disease (AD) participants were collected to measure protein levels of apoB and AD biomarkers amyloid beta (Aß), t-tau and p-tau, as well as synaptic markers GAP43, SYNAPTOTAGMIN-1, synaptosome associated protein 25 (SNAP-25), and NEUROGRANIN. CSF apoB levels were contrasted with positron emission tomography (PET) scan measures of Aß (18F-NAV4694) and Tau (flortaucipir) along with cognitive assessment alterations over 6 to 8 years. RESULTS: CSF apoB levels were elevated in AD participants and correlated with t-tau, p-tau, and the four synaptic markers in pre-symptomatic individuals. In the latter, CSF apoB levels correlated with PET flortaucipir-binding in entorhinal, parahippocampal, and fusiform regions. Baseline CSF apoB levels were associated with longitudinal visuospatial cognitive decline. DISCUSSION: CSF apoB markedly associates with early tau dysregulation in asymptomatic subjects and identifies at-risk individuals predisposed to develop visuospatial cognitive decline over time.

Association of a Total Cholesterol Polygenic Score with Cholesterol Levels and Pathological Biomarkers across the Alzheimer's Disease Spectrum.

Midlife hypercholesterolemia is a well-known risk factor for sporadic Alzheimer's disease (AD), and like AD, it is highly influenced by genetics with heritability estimates of 32-63%. We thus hypothesized that genetics underlying peripheral blood total cholesterol (TC) levels could influence the risk of developing AD. We created a weighted polygenic score (TC-PGS) using summary data from a meta-analysis of TC genome-wide association studies for evaluation in three independent AD-related cohorts spanning pre-clinical, clinical, and pathophysiologically proved AD. APOE-ε4 variant was purposely included in the analysis as it represents an already well-established genetic risk factor for both AD and circulating TC. We could vastly improve the performance of the score when considering p-value thresholds for inclusion in the score, sex, and statin use. This optimized score (p-value threshold of 1 × 10-6 for inclusion in the score) explained 18.2% of the variance in TC levels in statin free females compared to 6.9% in the entire sample and improved prediction of hypercholesterolemia (receiver operator characteristics analysis revealed area under the curve increase from 70.8% to 80.5%). The TC-PGS was further evaluated for association with AD risk and pathology. We found no association between the TC-PGS and either of the AD hallmark pathologies, assessed by cerebrospinal fluid levels of Aß-42, p-Tau, and t-Tau, and 18F-NAV4694 and 18F-AV-1451 positron emission tomography. Similarly, we found no association with the risk of developing amyloid pathology or becoming cognitively impaired in individuals with amyloid pathology.

The Biobanque québécoise de la COVID-19 (BQC19)-A cohort to prospectively study the clinical and biological determinants of COVID-19 clinical trajectories.

SARS-CoV-2 infection causing the novel coronavirus disease 2019 (COVID-19) has been responsible for more than 2.8 million deaths and nearly 125 million infections worldwide as of March 2021. In March 2020, the World Health Organization determined that the COVID-19 outbreak is a global pandemic. The urgency and magnitude of this pandemic demanded immediate action and coordination between local, regional, national, and international actors. In that mission, researchers require access to high-quality biological materials and data from SARS-CoV-2 infected and uninfected patients, covering the spectrum of disease manifestations. The "Biobanque québécoise de la COVID-19" (BQC19) is a pan-provincial initiative undertaken in Québec, Canada to enable the collection, storage and sharing of samples and data related to the COVID-19 crisis. As a disease-oriented biobank based on high-quality biosamples and clinical data of hospitalized and non-hospitalized SARS-CoV-2 PCR positive and negative individuals. The BQC19 follows a legal and ethical management framework approved by local health authorities. The biosamples include plasma, serum, peripheral blood mononuclear cells and DNA and RNA isolated from whole blood. In addition to the clinical variables, BQC19 will provide in-depth analytical data derived from the biosamples including whole genome and transcriptome sequencing, proteome and metabolome analyses, multiplex measurements of key circulating markers as well as anti-SARS-CoV-2 antibody responses. BQC19 will provide the scientific and medical communities access to data and samples to better understand, manage and ultimately limit, the impact of COVID-19. In this paper we present BQC19, describe the process according to which it is governed and organized, and address opportunities for future research collaborations. BQC19 aims to be a part of a global communal effort addressing the challenges of COVID-19.

Novel manifestations of Warburg micro syndrome type 1 caused by a new splicing variant of RAB3GAP1: a case report.

BACKGROUND: The present study aimed to determine the underlying genetic factors causing the possible Warburg micro syndrome (WARBM) phenotype in two Iranian patients. CASE PRESENTATION: A 5-year-old female and a 4.5-year-old male were referred due to microcephaly, global developmental delay, and dysmorphic features. After doing neuroimaging and clinical examinations, due to the heterogeneity of neurodevelopmental disorders, we subjected 7 family members to whole-exome sequencing. Three candidate variants were confirmed by Sanger sequencing and allele frequency of each variant was also determined in 300 healthy ethnically matched people using the tetra-primer amplification refractory mutation system-PCR and PCR-restriction fragment length polymorphism. To show the splicing effects, reverse transcription-PCR (RT-PCR) and RT-qPCR were performed, followed by Sanger sequencing. A novel homozygous variant-NM_012233.2: c.151-5 T > G; p.(Gly51IlefsTer15)-in the RAB3GAP1 gene was identified as the most likely disease-causing variant. RT-PCR/RT-qPCR showed that this variant can activate a cryptic site of splicing in intron 3, changing the splicing and gene expression processes. We also identified some novel manifestations in association with WARBM type 1 to touch upon abnormal philtrum, prominent antitragus, downturned corners of the mouth, malaligned teeth, scrotal hypoplasia, low anterior hairline, hypertrichosis of upper back, spastic diplegia to quadriplegia, and cerebral white matter signal changes. CONCLUSIONS: Due to the common phenotypes between WARBMs and Martsolf syndrome (MIM: 212720), we suggest using the "RABopathies" term that can in turn cover a broad range of manifestations. This study can per se increase the genotype-phenotype spectrum of WARBM type 1.

Whole genome sequencing identifies a duplicated region encompassing Xq13.2q13.3 in a large Iranian family with intellectual disability.

BACKGROUND: The X chromosome has historically been one of the most thoroughly investigated chromosomes regarding intellectual disability (ID), whose etiology is attributed to many factors including copy number variations (CNVs). Duplications of the long arm of the X chromosome have been reported in patients with ID, short stature, facial anomalies, and in many cases hypoplastic genitalia and/or behavioral abnormalities. METHODS: Here, we report on a large Iranian family with X-linked ID caused by a duplication on the X chromosome identified by whole genome sequencing in combination with linkage analysis. RESULTS: Seven affected males in different branches of the family presented with ID, short stature, seizures, facial anomalies, behavioral abnormalities (aggressiveness, self-injury, anxiety, impaired social interactions, and shyness), speech impairment, and micropenis. The duplication of the region Xq13.2q13.3, which is ~1.8 Mb in size, includes seven protein-coding OMIM genes. Three of these genes, namely SLC16A2, RLIM, and NEXMIF, if impaired, can lead to syndromes presenting with ID. Of note, this duplicated region was located within a linkage interval with a LOD score >3. CONCLUSION: Our report indicates that CNVs should be considered in multi-affected families where no candidate gene defect has been identified in sequencing data analysis.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) in Alzheimer's disease: A genetic and proteomic multi-cohort study.

BACKGROUND: Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a hepatic enzyme that regulates circulating low-density lipoprotein (LDL) cholesterol levels by binding to LDL receptors (LDLR) and promoting their degradation. Although PCSK9 inhibitors were shown to reduce the risk of cardiovascular disease, a warning was issued concerning their possible impact on cognitive functions. In Alzheimer's disease (AD), it is believed that cognitive impairment is associated with cholesterol metabolism alterations, which could involve PCSK9. The main objective of this study is to determine if PCSK9 plays a significant role in the pre-symptomatic phase of the disease when the pathophysiological markers of AD unfolds and, later, when cognitive symptoms emerge. METHODS AND FINDINGS: To test if PCSK9 is associated with AD pathology, we measured its expression levels in 65 autopsy confirmed AD brains and 45 age and gender matched controls. Messenger ribonucleic acid (mRNA) were quantified using real-time polymerase chain reaction (RT-PCR) and protein levels were quantified using enzyme-linked immunosorbent assay (ELISA). PCSK9 was elevated in frontal cortices of AD subjects compared to controls, both at the mRNA and protein levels. LDLR protein levels were unchanged in AD frontal cortices, despite and upregulation at the mRNA level. To verify if PCSK9 dysregulation was observable before the onset of AD, we measured its expression in the cerebrospinal fluid (CSF) of 104 "at-risk" subjects and contrasted it with known apolipoproteins levels and specific AD biomarkers using ELISAs. Positive correlations were found between CSF PCSK9 and apolipoprotein E (APOE), apolipoprotein J (APOJ or CLU), apolipoprotein B (APOB), phospho Tau (pTau) and total Tau. To investigate if PCSK9 levels were driven by genetic variants, we conducted an expression quantitative trait loci (eQTL) study using bioinformatic tools and found two polymorphisms in strong association. Further investigation of these variants in two independent cohorts showed a female specific association with AD risk and with CSF Tau levels in cognitively impaired individuals. CONCLUSIONS: PCSK9 levels differ between control and AD brains and its protein levels correlate with those of other lipoproteins and AD biomarkers even before the onset of the disease. PCSK9 regulation seems to be under tight genetic control in females only, with specific variants that could predispose to increased AD risk.

Association of PPP2R1A with Alzheimer's disease and specific cognitive domains.

In an attempt to identify novel genetic variants associated with sporadic Alzheimer's disease (AD), a genome-wide association study was performed on a population isolate from Eastern Canada, referred to as the Québec Founder Population (QFP). In the QFP cohort, the rs10406151 C variant on chromosome 19 is associated with higher AD risk and younger age at AD onset in APOE4- individuals. After surveying the region surrounding this intergenic polymorphism for brain cis-eQTL associations in BRAINEAC, we identified PPP2R1A as the most likely target gene modulated by the rs10406151 C variant. PPP2R1A mRNA and protein levels are elevated in multiple regions from QFP autopsy-confirmed AD brains when compared with age-matched controls. Using an independent cohort of cognitively normal individuals with a parental history of AD, we found that the rs10406151 C variant is significantly associated with lower visuospatial and constructional performances. The association of the rs10406151 C variant with AD risk appears to involve brain PPP2R1A gene expression alterations. However, the exact pathological pathway by which this variant modulates AD remains elusive.

Association of TLR4 with Alzheimer's disease risk and presymptomatic biomarkers of inflammation.

INTRODUCTION: A coding variant in the TLR4 receptor (rs4986790), previously associated with longevity and Alzheimer's disease (AD) risk reduction, was examined in a population isolate (Québec Founder Population [QFP]) and in presymptomatic individuals with a parental history of AD (Pre-Symptomatic Evaluation of Novel or Experimental Treatment for Alzheimer's Disease [PREVENT-AD]). METHODS: Genotyping was performed using the Illumina HumanHap 550k (QFP) and the Illumina Omni2.5 beadchips (PREVENT-AD). Cognition was assessed using the Repeatable Battery for Assessment of Neuropsychological Status (RBANS). Whole-brain cortical thickness data were analyzed using CIVET 1.12. Cerebrospinal fluid concentrations of cytokines were obtained by using Milliplex. RESULTS: The minor allele of the rs4986790 polymorphism (G) is associated with a reduced risk of developing AD in the QFP, as well as higher visuospatial and constructional abilities, higher cortical thickness in visual-related regions, and stable cerebrospinal fluid IL-1ß levels in the PREVENT-AD cohort. DISCUSSION: The rs4986790 G coding variant in the TLR4 gene appears to reduce AD risk through the modulation of IL-1ß synthesis and secretion in the presymptomatic phase of the disease.

Expression of DRD2 Is Increased in Human Pancreatic Ductal Adenocarcinoma and Inhibitors Slow Tumor Growth in Mice.

BACKGROUND & AIMS: Incidence of and mortality from pancreatic ductal adenocarcinoma (PDAC), the most common form of pancreatic cancer, are almost equivalent, so better treatments are needed. We studied gene expression profiles of PDACs and the functions of genes with altered expression to identify new therapeutic targets. METHODS: We performed microarray analysis to analyze gene expression profiles of 195 PDAC and 41 non-tumor pancreatic tissue samples. We undertook an extensive analysis of the PDAC transcriptome by superimposing interaction networks of proteins encoded by aberrantly expressed genes over signaling pathways associated with PDAC development to identify factors that might alter regulation of these pathways during tumor progression. We performed tissue microarray analysis to verify changes in expression of candidate protein using an independent set of 152 samples (40 nontumor pancreatic tissues, 63 PDAC sections, and 49 chronic pancreatitis samples). We validated the functional relevance of the candidate molecule using RNA interference or pharmacologic inhibitors in pancreatic cancer cell lines and analyses of xenograft tumors in mice. RESULTS: In an analysis of 38,276 human genes and loci, we identified 1676 genes that were significantly up-regulated and 1166 genes that were significantly down-regulated in PDAC compared with nontumor pancreatic tissues. One gene that was up-regulated and associated with multiple signaling pathways that are dysregulated in PDAC was G protein subunit αi2, which has not been previously associated with PDAC. G protein subunit αi2 mediates the effects of dopamine receptor D2 (DRD2) on cyclic adenosine monophosphate signaling; PDAC tissues had a slight but significant increase in DRD2 messenger RNA. Levels of DRD2 protein were substantially increased in PDACs, compared with non-tumor tissues, in tissue microarray analyses. RNA interference knockdown of DRD2 or inhibition with pharmacologic antagonists (pimozide and haloperidol) reduced proliferation of pancreatic cancer cells, induced endoplasmic reticulum stress and apoptosis, and reduced cell migration. RNA interference knockdown of DRD2 in pancreatic tumor cells reduced growth of xenograft tumors in mice, and administration of the DRD2 inhibitor haloperidol to mice with orthotopic xenograft tumors reduced final tumor size and metastasis. CONCLUSIONS: In gene expression profile analysis of PDAC samples, we found the DRD2 signaling pathway to be activated. Inhibition of DRD2 in pancreatic cancer cells reduced proliferation and migration, and slowed growth of xenograft tumors in mice. DRD2 antagonists routinely used for management of schizophrenia might be tested in patients with pancreatic cancer.

Screening of dementia genes by whole-exome sequencing in early-onset Alzheimer disease: input and lessons.

Causative variants in APP, PSEN1 or PSEN2 account for a majority of cases of autosomal dominant early-onset Alzheimer disease (ADEOAD, onset before 65 years). Variant detection rates in other EOAD patients, that is, with family history of late-onset AD (LOAD) (and no incidence of EOAD) and sporadic cases might be much lower. We analyzed the genomes from 264 patients using whole-exome sequencing (WES) with high depth of coverage: 90 EOAD patients with family history of LOAD and no incidence of EOAD in the family and 174 patients with sporadic AD starting between 51 and 65 years. We found three PSEN1 and one PSEN2 causative, probably or possibly causative variants in four patients (1.5%). Given the absence of PSEN1, PSEN2 and APP causative variants, we investigated whether these 260 patients might be burdened with protein-modifying variants in 20 genes that were previously shown to cause other types of dementia when mutated. For this analysis, we included an additional set of 160 patients who were previously shown to be free of causative variants in PSEN1, PSEN2 and APP: 107 ADEOAD patients and 53 sporadic EOAD patients with an age of onset before 51 years. In these 420 patients, we detected no variant that might modify the function of the 20 dementia-causing genes. We conclude that EOAD patients with family history of LOAD and no incidence of EOAD in the family or patients with sporadic AD starting between 51 and 65 years have a low variant-detection rate in AD genes.

Neurotrophins modulate neuron-glia interactions at a vertebrate synapse.

Neurotrophins are important modulators of synaptic function at both developing and mature synapses in the CNS and PNS. At the neuromuscular junction (NMJ), neurotrophins, as well as perisynaptic Schwann cells (PSCs) are critical for the long-term maintenance and stability of the synapse. Considering this correlation and the acute interactions that occur at the synapse between PSCs and the nerve terminal, we wondered if neurotrophins could also be involved in neuron-glia signalling. To test if neurotrophins were able to signal to PSCs we used brief applications of neurotrophin-3 (NT-3), brain-derived neurotophic factor (BDNF) or nerve growth factor (NGF; 100 ng/mL). Soleus muscles of mice were incubated with the Ca(2+) indicator Fluo-4AM and Ca(2+) responses in PSCs were elicited through nerve stimulation (50 Hz, 30 s). Our results indicate that acute application of both NT-3 and BDNF, but not NGF, increased PSC Ca(2+) responses. Investigation of the mechanisms involved in these increases revealed distinct pathways for BDNF and NT-3. BDNF increased PSC responsiveness through potentiation of ATP responses while NT-3 modulated muscarinic acetylcholine receptor signalling. Using local applications of the neurotrophins, we found that both neurotrophins were able to elicit Ca(2+) responses in PSCs where BDNF used a phospholipase C-inositol 1,4,5-triphosphate (PLC-IP(3)) mechanism, while NT-3 required extracellular Ca(2+). Our results demonstrate a neurotrophin-dependent modulation of neuron-glia signalling through differential mechanisms employed by NT-3 and BDNF. Hence, neurotrophins precisely and differentially regulate PSC functions through modulation of either purinergic or cholinergic signalling pathways.

p75 neurotrophin receptor reduces ligand-induced Trk receptor ubiquitination and delays Trk receptor internalization and degradation.

Target-derived neurotrophins regulate neuronal survival and growth by interacting with cell-surface tyrosine kinase receptors. The p75 neurotrophin receptor (p75 NTR) is coexpressed with Trk receptors in long-range projection neurons, in which it facilitates neurotrophin binding to Trk and enhances Trk activity. Here, we show that TrkA and TrkB receptors undergo robust ligand-dependent ubiquitination that is dependent on activation of the endogenous Trk activity of the receptors. Coexpression of p75 NTR attenuated ubiquitination of TrkA and TrkB and delayed nerve growth factor-induced TrkA receptor internalization and receptor degradation. These results indicate that p75 NTR may prolong cell-surface Trk-dependent signalling events by negatively regulating receptor ubiquitination.

Glial cells and neurotransmission: an inclusive view of synaptic function.

Glial cells throughout the nervous system are closely associated with synapses. Accompanying these anatomical couplings are intriguing functional interactions, including the capacity of certain glial cells to respond to and modulate neurotransmission. Glial cells can also help establish, maintain, and reconstitute synapses. In this review, we discuss evidence indicating that glial cells make important contributions to synaptic function.

Perisynaptic Schwann cells at the neuromuscular junction: nerve- and activity-dependent contributions to synaptic efficacy, plasticity, and reinnervation.

Glial cells are increasingly recognized for their important contributions to CNS and PNS synaptic function. Perisynaptic Schwann cells, which are glial cells at the neuromuscular junction, have proven to be an exceptionally useful model for studying these roles. Recent studies have shown that they detect and reciprocally modulate synaptic efficacy in an activity-dependent manner in the short term. In addition, perisynaptic Schwann cells guide reinnervating nerve sprouts after deinnervation, and many important parameters of this are dependent on synapse activity. Thus, it is hypothesized that perisynaptic Schwann cells are key integrators in a continuum of synaptic efficacy, stability, and plasticity at the neuromuscular junction, which is important for maintaining and restoring synaptic efficacy.

Modulation of neurotransmission by reciprocal synapse-glial interactions at the neuromuscular junction.

Perisynaptic Schwann cells are glial cells that are closely associated with pre- and postsynaptic elements of the neuromuscular junction. Recent evidence shows that these cells detect and modulate neurotransmission in an activity-dependent fashion. Through G-protein signalling and Ca(2+) released from internal stores they can decrease or increase neurotransmitter release, respectively. Thus, they help to establish the level of neurotransmission associated with activity dependent short-term synaptic plasticity. We discuss evidence implicating perisynaptic Schwann cells as being active partners in neurotransmission at the neuromuscular junction, with emphasis on the modulation of short-term plasticity and potential implications for long-term changes.

Alzheimer's disease and the basal forebrain cholinergic system: relations to beta-amyloid peptides, cognition, and treatment strategies.

Alzheimer's disease (AD) is the most common form of degenerative dementia and is characterized by progressive impairment in cognitive function during mid- to late-adult life. Brains from AD patients show several distinct neuropathological features, including extracellular beta-amyloid-containing plaques, intracellular neurofibrillary tangles composed of abnormally phosphorylated tau, and degeneration of cholinergic neurons of the basal forebrain. In this review, we will present evidence implicating involvement of the basal forebrain cholinergic system in AD pathogenesis and its accompanying cognitive deficits. We will initially discuss recent results indicating a link between cholinergic mechanisms and the pathogenic events that characterize AD, notably amyloid-beta peptides. Following this, animal models of dementia will be discussed in light of the relationship between basal forebrain cholinergic hypofunction and cognitive impairments in AD. Finally, past, present, and future treatment strategies aimed at alleviating the cognitive symptomatology of AD by improving basal forebrain cholinergic function will be addressed.