Alzheimer's Association's funding portfolio: Insights from the International Alzheimer's and Related Dementias Research Portfolio (IADRP).

Introduction: Alzheimer's disease (AD) and related dementias (ADRD) present significant health challenges. Understanding their underlying biology, advancing existing and new therapies, and enhancing care for patients and caregivers are critical priorities.

Methods: This article utilizes data from the International Alzheimer's and Related Dementias Research Portfolio (IADRP) to analyze funding patterns from the Alzheimer's Association over the past decade.

Long-term Clinical Outcomes of Patients With Medullary Thyroid Cancer: A Single Institution, Tertiary Referral Centre Experience.

Aims: Medullary thyroid cancer (MTC) is a rare form of thyroid cancer with a variable disease course. We aimed to conduct a real-world analysis of the clinical outcomes of patients with MTC, thereby providing further insight into the prognosis and management.

Materials And Methods: All patients with MTC whose data were available on electronic patient records since its introduction in 1992 at our institution were collected retrospectively.

The impact of astrocytic NF-κB on healthy and Alzheimer's disease brains.

Astrocytes play a role in healthy cognitive function and Alzheimer's disease (AD). The transcriptional factor nuclear factor-κB (NF-κB) drives astrocyte diversity, but the mechanisms are not fully understood. By combining studies in human brains and animal models and selectively manipulating NF-κB function in astrocytes, we deepened the understanding of the role of astrocytic NF-κB in brain health and AD.

Sex-specific associations between AD genotype and the microbiome of human amyloid beta knock-in (hAβ-KI) mice.

Introduction: Emerging evidence links changes in the gut microbiome to late-onset Alzheimer's disease (LOAD), necessitating examination of AD mouse models with consideration of the microbiome.

Methods: We used shotgun metagenomics and untargeted metabolomics to study the human amyloid beta knock-in (hAβ-KI) murine model for LOAD compared to both wild-type (WT) mice and a model for early-onset AD (3xTg-AD).

Results: Eighteen-month female (but not male) hAβ-KI microbiomes were distinct from WT microbiomes, with AD genotype accounting for 18% of the variance by permutational multivariate analysis of variance (PERMANOVA).

Cross-species comparative hippocampal transcriptomics in Alzheimer's disease.

Unlabelled: Alzheimer's disease (AD) is a multifactorial pathology, with most cases having a sporadic origin. Recently, knock-in (KI) mouse models, such as the novel humanized amyloid-β (hAβ)-KI, have been developed to better resemble sporadic human AD.

Methods: Here, we compared hippocampal publicly available transcriptomic profiles of transgenic (5xFAD and APP/PS1) and KI (hAβ-KI) mouse models with early- (EOAD) and late- (LOAD) onset AD patients.

A Trem2 mouse model without cryptic splicing drives age- and disease-dependent tissue damage and synaptic loss in response to plaques.

Background: The TREM2 R47H variant is one of the strongest genetic risk factors for late-onset Alzheimer's Disease (AD). Unfortunately, many current Trem2 mouse models are associated with cryptic mRNA splicing of the mutant allele that produces a confounding reduction in protein product. To overcome this issue, we developed the Trem2 (Normal Splice Site) mouse model in which the Trem2 allele is expressed at a similar level to the wild-type Trem2 allele without evidence of cryptic splicing products.

Longitudinal Analysis of the Microbiome and Metabolome in the 5xfAD Mouse Model of Alzheimer's Disease.

Recent reports implicate gut microbiome dysbiosis in the onset and progression of Alzheimer's disease (AD), yet studies involving model animals overwhelmingly omit the microbial perspective. Here, we evaluate longitudinal microbiomes and metabolomes from a popular transgenic mouse model for familial AD (5xfAD). Cecal and fecal samples from 5xfAD and wild-type B6J (WT) mice from 4 to 18 months of age were subjected to shotgun Illumina sequencing.

SPG302 Reverses Synaptic and Cognitive Deficits Without Altering Amyloid or Tau Pathology in a Transgenic Model of Alzheimer's Disease.

Alzheimer's disease (AD) is conceptualized as a synaptic failure disorder in which loss of glutamatergic synapses is a major driver of cognitive decline. Thus, novel therapeutic strategies aimed at regenerating synapses may represent a promising approach to mitigate cognitive deficits in AD patients. At present, no disease-modifying drugs exist for AD, and approved therapies are palliative at best, lacking in the ability to reverse the synaptic failure.

Generation of a humanized Aβ expressing mouse demonstrating aspects of Alzheimer's disease-like pathology.

The majority of Alzheimer's disease (AD) cases are late-onset and occur sporadically, however most mouse models of the disease harbor pathogenic mutations, rendering them better representations of familial autosomal-dominant forms of the disease. Here, we generated knock-in mice that express wildtype human Aβ under control of the mouse App locus. Remarkably, changing 3 amino acids in the mouse Aβ sequence to its wild-type human counterpart leads to age-dependent impairments in cognition and synaptic plasticity, brain volumetric changes, inflammatory alterations, the appearance of Periodic Acid-Schiff (PAS) granules and changes in gene expression.

Baseline neuropsychological profiles in prion disease predict survival time.

Objective: Few studies have captured the neuropsychological profile of sporadic Creutzfeldt-Jakob disease (sCJD) with neuropsychological testing, and little is known about cognitive predictors of survival. We characterized baseline neuropsychological performance in sCJD and investigated associations with survival.

Methods: sCJD participants who completed the MMSE (n = 118), 61 sCJD of whom also completed a neuropsychological battery at baseline, and 135 age-matched healthy controls, were included.

Model organism development and evaluation for late-onset Alzheimer's disease: MODEL-AD.

Alzheimer's disease (AD) is a major cause of dementia, disability, and death in the elderly. Despite recent advances in our understanding of the basic biological mechanisms underlying AD, we do not know how to prevent it, nor do we have an approved disease-modifying intervention. Both are essential to slow or stop the growth in dementia prevalence.

miR-181a negatively modulates synaptic plasticity in hippocampal cultures and its inhibition rescues memory deficits in a mouse model of Alzheimer's disease.

MicroRNAs play a pivotal role in rapid, dynamic, and spatiotemporal modulation of synaptic functions. Among them, recent emerging evidence highlights that microRNA-181a (miR-181a) is particularly abundant in hippocampal neurons and controls the expression of key plasticity-related proteins at synapses. We have previously demonstrated that miR-181a was upregulated in the hippocampus of a mouse model of Alzheimer's disease (AD) and correlated with reduced levels of plasticity-related proteins.

Intra- and extracellular β-amyloid overexpression via adeno-associated virus-mediated gene transfer impairs memory and synaptic plasticity in the hippocampus.

Alzheimer's disease (AD), the most common age-related neurodegenerative disorder, is currently conceptualized as a disease of synaptic failure. Synaptic impairments are robust within the AD brain and better correlate with dementia severity when compared with other pathological features of the disease. Nevertheless, the series of events that promote synaptic failure still remain under debate, as potential triggers such as β-amyloid (Aβ) can vary in size, configuration and cellular location, challenging data interpretation in causation studies.

Astrocytes: From the Physiology to the Disease.

Astrocytes are key cells for adequate brain formation and regulation of cerebral blood flow as well as for the maintenance of neuronal metabolism, neurotransmitter synthesis and exocytosis, and synaptic transmission. Many of these functions are intrinsically related to neurodegeneration, allowing refocusing on the role of astrocytes in physiological and neurodegenerative states. Indeed, emerging evidence in the field indicates that abnormalities in the astrocytic function are involved in the pathogenesis of multiple neurodegenerative diseases, including Alzheimer's Disease (AD), Parkinson's Disease (PD), Huntington's Disease (HD) and Amyotrophic Lateral Sclerosis (ALS).

Tau underlies synaptic and cognitive deficits for type 1, but not type 2 diabetes mouse models.

Diabetes mellitus (DM) is one of the most devastating diseases that currently affects the aging population. Recent evidence indicates that DM is a risk factor for many brain disorders, due to its direct effects on cognition. New findings have shown that the microtubule-associated protein tau is pathologically processed in DM; however, it remains unknown whether pathological tau modifications play a central role in the cognitive deficits associated with DM.

Past to Future: What Animal Models Have Taught Us About Alzheimer's Disease.

Alzheimer's disease (AD) impairs memory and causes significant cognitive deficits. The disease course is prolonged, with a poor prognosis, and thus exacts an enormous economic and social burden. Over the past two decades, genetically engineered mouse models have proven indispensable for understanding AD pathogenesis, as well as for discovering new therapeutic targets.

Genetic PrP Prion Diseases.

Genetic prion diseases (gPrDs) caused by mutations in the prion protein gene () have been classified as genetic Creutzfeldt-Jakob disease, Gerstmann-Sträussler-Scheinker disease, or fatal familial insomnia. Mutations in can be missense, nonsense, and/or octapeptide repeat insertions or, possibly, deletions. These mutations can produce diverse clinical features.

Delayed decompression exacerbates ischemia-reperfusion injury in cervical compressive myelopathy.

Degenerative cervical myelopathy (DCM) is the most common progressive nontraumatic spinal cord injury. The most common recommended treatment is surgical decompression, although the optimal timing of intervention is an area of ongoing debate. The primary objective of this study was to assess whether a delay in decompression could influence the extent of ischemia-reperfusion injury and alter the trajectory of outcome in DCM.

Synaptic Impairment in Alzheimer's Disease: A Dysregulated Symphony.

Alzheimer's disease (AD) is characterized by memory loss, cognitive decline, and devastating neurodegeneration, not only as a result of the extracellular accumulation of beta-amyloid peptide (Aβ) and intracellular accumulation of tau, but also as a consequence of the dysfunction and loss of synapses. Although significant advances have been made in our understanding of the relationship of the pathological role of Aβ and tau in synapse dysfunction, several questions remain as to how Aβ and tau interdependently cause impairments in synaptic function in AD. Overall, more insight into these questions should enable researchers in this field to develop novel therapeutic targets to mitigate or delay the cognitive deficits associated with this devastating disease.