The 2022 symposium on dementia and brain aging in low- and middle-income countries: Highlights on research, diagnosis, care, and impact.

Two of every three persons living with dementia reside in low- and middle-income countries (LMICs). The projected increase in global dementia rates is expected to affect LMICs disproportionately. However, the majority of global dementia care costs occur in high-income countries (HICs), with dementia research predominantly focusing on HICs.

Mutation of the ALS-/FTD-Associated RNA-Binding Protein FUS Affects Axonal Development.

Aberrant condensation and localization of the RNA-binding protein (RBP) fused in sarcoma (FUS) occur in variants of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Changes in RBP function are commonly associated with changes in axonal cytoskeletal organization and branching in neurodevelopmental disorders. Here, we asked whether branching defects also occur in vivo in a model of FUS-associated disease.

Regulation of membrane fluidity by RNF145-triggered degradation of the lipid hydrolase ADIPOR2.

The regulation of membrane lipid composition is critical for cellular homeostasis. Cells are particularly sensitive to phospholipid saturation, with increased saturation causing membrane rigidification and lipotoxicity. How mammalian cells sense membrane lipid composition and reverse fatty acid (FA)-induced membrane rigidification is poorly understood.

Reactive or transgenic increase in microglial TYROBP reveals a TREM2-independent TYROBP-APOE link in wild-type and Alzheimer's-related mice.

Introduction: Microglial TYROBP (DAP12) is a network hub and driver in sporadic late-onset Alzheimer's disease (AD). TYROBP is a cytoplasmic adaptor for TREM2 and other receptors, but little is known about its roles and actions in AD. Herein, we demonstrate that endogenous Tyrobp transcription is specifically increased in recruited microglia.

Inherited and Sporadic Amyotrophic Lateral Sclerosis and Fronto-Temporal Lobar Degenerations arising from Pathological Condensates of Phase Separating Proteins.

Recent work on the biophysics of proteins with low complexity, intrinsically disordered domains that have the capacity to form biological condensates has profoundly altered the concepts about the pathogenesis of inherited and sporadic neurodegenerative disorders associated with pathological accumulation of these proteins. In the present review, we use the FUS, TDP-43 and A11 proteins as examples to illustrate how missense mutations and aberrant post-translational modifications of these proteins cause amyotrophic lateral sclerosis (ALS) and fronto-temporal lobar degeneration (FTLD).

Integrative approach to sporadic Alzheimer's disease: deficiency of TYROBP in a tauopathy mouse model reduces C1q and normalizes clinical phenotype while increasing spread and state of phosphorylation of tau.

TYROBP/DAP12 forms complexes with ectodomains of immune receptors (TREM2, SIRPβ1, CR3) associated with Alzheimer's disease (AD) and is a network hub and driver in the complement subnetwork identified by multi-scale gene network studies of postmortem human AD brain. Using transgenic or viral approaches, we characterized in mice the effects of TYROBP deficiency on the phenotypic and pathological evolution of tauopathy. Biomarkers usually associated with worsening clinical phenotype (i.

TREM2 shedding by cleavage at the H157-S158 bond is accelerated for the Alzheimer's disease-associated H157Y variant.

We have characterised the proteolytic cleavage events responsible for the shedding of triggering receptor expressed on myeloid cells 2 (TREM2) from primary cultures of human macrophages, murine microglia and TREM2-expressing human embryonic kidney (HEK293) cells. In all cell types, a soluble 17 kDa N-terminal cleavage fragment was shed into the conditioned media in a constitutive process that is inhibited by G1254023X and metalloprotease inhibitors and siRNA targeting ADAM10. Inhibitors of serine proteases and matrix metalloproteinases 2/9, and ADAM17 siRNA did not block TREM2 shedding.

Structural and Chemical Biology of Presenilin Complexes.

The presenilin proteins are the catalytic subunits of a tetrameric complex containing presenilin 1 or 2, anterior pharynx defective 1 (APH1), nicastrin, and PEN-2. Other components such as TMP21 may exist in a subset of specialized complexes. The presenilin complex is the founding member of a unique class of aspartyl proteases that catalyze the γ, ɛ, ζ site cleavage of the transmembrane domains of Type I membrane proteins including amyloid precursor protein (APP) and Notch.

Transethnic genome-wide scan identifies novel Alzheimer's disease loci.

Introduction: Genetic loci for Alzheimer's disease (AD) have been identified in whites of European ancestry, but the genetic architecture of AD among other populations is less understood.

Methods: We conducted a transethnic genome-wide association study (GWAS) for late-onset AD in Stage 1 sample including whites of European Ancestry, African-Americans, Japanese, and Israeli-Arabs assembled by the Alzheimer's Disease Genetics Consortium. Suggestive results from Stage 1 from novel loci were followed up using summarized results in the International Genomics Alzheimer's Project GWAS dataset.

ALS5/SPG11/KIAA1840 mutations cause autosomal recessive axonal Charcot-Marie-Tooth disease.

Charcot-Marie-Tooth disease is a group of hereditary peripheral neuropathies that share clinical characteristics of progressive distal muscle weakness and atrophy, foot deformities, distal sensory loss, as well as diminished tendon reflexes. Hundreds of causative DNA changes have been found, but much of the genetic basis of the disease is still unexplained. Mutations in the ALS5/SPG11/KIAA1840 gene are a frequent cause of autosomal recessive hereditary spastic paraplegia with thin corpus callosum and peripheral axonal neuropathy, and account for ∼ 40% of autosomal recessive juvenile amyotrophic lateral sclerosis.

Structural biology of presenilin 1 complexes.

The presenilin genes were first identified as the site of missense mutations causing early onset autosomal dominant familial Alzheimer's disease. Subsequent work has shown that the presenilin proteins are the catalytic subunits of a hetero-tetrameric complex containing APH1, nicastrin and PEN-2. This complex (variously termed presenilin complex or gamma-secretase complex) performs an unusual type of proteolysis in which the transmembrane domains of Type I proteins are cleaved within the hydrophobic compartment of the membrane.

Early fear memory defects are associated with altered synaptic plasticity and molecular architecture in the TgCRND8 Alzheimer's disease mouse model.

Alzheimer's disease (AD) is a complex and slowly progressing dementing disorder that results in neuronal and synaptic loss, deposition in brain of aberrantly folded proteins, and impairment of spatial and episodic memory. Most studies of mouse models of AD have employed analyses of cognitive status and assessment of amyloid burden, gliosis, and molecular pathology during disease progression. Here we sought to understand the behavioral, cellular, ultrastructural, and molecular changes that occur at a pathological stage equivalent to the early stages of human AD.

Structural interactions between inhibitor and substrate docking sites give insight into mechanisms of human PS1 complexes.

Presenilin-mediated endoproteolysis of transmembrane proteins plays a key role in physiological signaling and in the pathogenesis of Alzheimer disease and some cancers. Numerous inhibitors have been found via library screens, but their structural mechanisms remain unknown. We used several biophysical techniques to investigate the structure of human presenilin complexes and the effects of peptidomimetic γ-secretase inhibitors.

The isotropic fractionator provides evidence for differential loss of hippocampal neurons in two mouse models of Alzheimer's disease.

Background: The accumulation of amyloid beta (Aβ) oligomers or fibrils is thought to be one of the main causes of synaptic and neuron loss, believed to underlie cognitive dysfunction in Alzheimer's disease (AD). Neuron loss has rarely been documented in amyloid precursor protein (APP) transgenic mouse models. We investigated whether two APP mouse models characterized by different folding states of amyloid showed different neuronal densities using an accurate method of cell counting.

SQSTM1 mutations in frontotemporal lobar degeneration and amyotrophic lateral sclerosis.

Objective: There is increasing evidence that common genetic risk factors underlie frontotemporal lobar degeneration (FTLD) and amyotrophic lateral sclerosis (ALS). Recently, mutations in the sequestosome 1 (SQSTM1) gene, which encodes p62 protein, have been reported in patients with ALS. P62 is a multifunctional adapter protein mainly involved in selective autophagy, oxidative stress response, and cell signaling pathways.

Meta-analysis of the association between variants in SORL1 and Alzheimer disease.

Objective: To reexamine the association between the neuronal sortilin-related receptor gene (SORL1) and Alzheimer disease (AD).

Design: Comprehensive and unbiased meta-analysis of all published and unpublished data from case-control studies for the SORL1 single-nucleotide polymorphisms (SNPs) that had been repeatedly assessed across studies.

Setting: Academic research institutions in the United States, the Netherlands, Canada, Belgium, the United Kingdom, Singapore, Japan, Sweden, Germany, France, and Italy.

Family reunion--the ZIP/prion gene family.

Prion diseases are fatal neurodegenerative diseases of humans and animals which, in addition to sporadic and familial modes of manifestation, can be acquired via an infectious route of propagation. In disease, the prion protein (PrP(C)) undergoes a structural transition to its disease-causing form (PrP(Sc)) with profoundly different physicochemical properties. Surprisingly, despite intense interest in the prion protein, its function in the context of other cellular activities has largely remained elusive.

Identification of novel loci for Alzheimer disease and replication of CLU, PICALM, and BIN1 in Caribbean Hispanic individuals.

Objectives: To identify novel loci for late-onset Alzheimer disease (LOAD) in Caribbean Hispanic individuals and to replicate the findings in a publicly available data set from the National Institute on Aging Late-Onset Alzheimer's Disease Family Study.

Design: Nested case-control genome-wide association study.

Setting: The Washington Heights-Inwood Columbia Aging Project and the Estudio Familiar de Influencia Genetica de Alzheimer study.

Group II metabotropic glutamate receptor stimulation triggers production and release of Alzheimer's amyloid(beta)42 from isolated intact nerve terminals.

Aberrant accumulation of amyloid beta (Abeta) oligomers may underlie the cognitive failure of Alzheimer's disease (AD). All species of Abeta peptides are produced physiologically during normal brain activity. Therefore, elucidation of mechanisms that interconnect excitatory glutamatergic neurotransmission, synaptic amyloid precursor protein (APP) processing and production of its metabolite, Abeta, may reveal synapse-specific strategies for suppressing the pathological accumulation of Abeta oligomers and fibrils that characterize AD.

SPATACSIN mutations cause autosomal recessive juvenile amyotrophic lateral sclerosis.

The mutation of the spatacsin gene is the single most common cause of autosomal recessive hereditary spastic paraplegia with thin corpus callosum. Common clinical, pathological and genetic features between amyotrophic lateral sclerosis and hereditary spastic paraplegia motivated us to investigate 25 families with autosomal recessive juvenile amyotrophic lateral sclerosis and long-term survival for mutations in the spatascin gene. The inclusion criterion was a diagnosis of clinically definite amyotrophic lateral sclerosis according to the revised El Escorial criteria.

Association of distinct variants in SORL1 with cerebrovascular and neurodegenerative changes related to Alzheimer disease.

Background: Single-nucleotide polymorphisms (SNPs) in 2 distinct regions of the gene for the sortilin-related receptor (SORL1) (bounded by consecutively numbered SNPs 8-10 and 22-25) were shown to be associated with Alzheimer disease (AD) in multiple ethnically diverse samples.

Objective: To test the hypothesis that SORL1 is associated with brain magnetic resonance imaging (MRI) measurements of atrophy and/or vascular disease.

Design, Setting, And Patients: We evaluated the association of 30 SNPs spanning SORL1 with MRI measures of general cerebral atrophy, hippocampal atrophy, white matter hyperintensities, and overall cerebrovascular disease in 44 African American and 182 white sibships from the MIRAGE Study.