David Baglietto-Vargas

Alzheimer's disease (AD) is a complex disorder involving multiple cellular and molecular mechanisms. Recent evidence suggests that metabolic alterations play a crucial role in AD progression. Likewise, diabetes and obesity-two major metabolic diseases-are well-established risk factors for AD. These conditions are associated with a significant expansion of white adipose tissue (WAT). Here, we hypothesize that visceral WAT may act as a key mediator between peripheral metabolic dysfunction and brain illnesses. Immunohistochemistry and biochemical approaches were used to evaluate the WAT from WT and db/db mice. Similar techniques were applied to examine the brain tissue of 3xTg-AD mice that received white epididymal fat pads from WT or db/db donors and determine the impact of adipose tissue transplantation on tau and Aβ pathology. Our study revealed that recipient 3xTg-AD mice that received db/db fat pads developed profound changes in tau pathology due to increased expression of the cyclin-dependent kinase 5 activator p25 compared with 3xTg-AD mice that received fad pads from WT or sham mice. This increment in p25/cdk5 was associated with a prominent inflammatory response induced by the WAT transplant. Moreover, the opposite effect on Aβ pathology was found. The reduction in Aβ levels was correlated with an increase in microglial phagocytic capacity. Overall, our study demonstrated a novel crosstalk between AD and metabolic disorders through white adipose signaling resulting in differential effects on tau and Aβ pathology mediated by an activated immune response.

Alzheimer's disease (AD) is a complex neurodegenerative proteinopathy in which Aβ and tau misfold and aggregate into entities that structurally unsettle native proteins, mimicking a prion‐like or “seeding” process. These Aβ and tau “seeds” can arrange in different conformations or strains that might display distinct pathogenic properties. Furthermore, recent evidence suggests that microglia play a key role in the amyloidogenic event and can modulate the propagation and aggregation processes. Here, we employed histological and molecular approaches to determine whether seeds from human AD brains compared to those from transgenic mice (3xTg‐AD) are more prone to induce Aβ and tau aggregates in vivo, as well as potential differences in the microglial response to the plaque pathology. Brain homogenates were injected into the hippocampus of 3xTg‐AD mice and hAβ‐KI mice and examined at 18–20 months of age. The seeds from the human AD brain induced more aggressive amyloid pathology compared to seeds from aged 3xTg‐AD mice. However, the AD seeds from aged transgenic mice triggered more tau pathology. Interestingly, such mice seeds impaired microglial clustering around plaques, leading to more severe neuritic pathology. Furthermore, the human AD seeds injected into the hippocampus of hAβ‐KI mice were not able to induce plaque formation. These results suggest that multiple variables such as the AD seed, recipient model, and time are critical factors that can modulate the amyloid pathology onset and progression. Thus, more profound understanding of these factors will provide key insight into how amyloid and tau pathology progresses in AD.

SignificanceAlzheimer’s disease (AD) is an age-related neurodegenerative disorder with cerebrovascular alterations contributing to cognitive decline. Assessing cerebrovascular changes in mouse models that mimic the human condition of late-onset, sporadic AD is important for better human applicability.AimTo assess cerebrovascular changes in three mouse models: (1) 3xTg-AD; (2) the humanized amyloid-beta knock-in (hAβ-KI) mouse model of late-onset, sporadic AD; and (3) age-matched wild-type mice.ApproachWe measured resting-state cerebral blood flow (CBF) and neurovascular coupling (NVC) using laser speckle imaging (LSI) and performed ex vivo analyses of gene expression and cerebrovascular structure using bulk ribonucleic acid sequencing and confocal microscopy, respectively.ResultsOur study identifies specific cerebrovascular alterations in the hAβ-KI mouse model, including increased resting-state CBF, a shift toward smaller blood vessel diameters, impaired NVC, and transcriptomic changes related to metabolism and inflammation. Notably, we found that the increased resting-state CBF was primarily associated with female hAβ-KI mice.ConclusionsOur findings demonstrate that the hAβ-KI mouse model exhibits cerebrovascular alterations that warrant further investigation to uncover the underlying mechanisms. Expanding these studies could enhance our understanding of cerebrovascular alterations in AD and support the development of targeted therapeutic strategies.

Animal and cellular models have been essential tools over the years to understand many pathogenic mechanisms underlying different neurodegenerative disorders (NDDs), including Alzheimer’s disease (AD)

Adipose tissue has recently been recognized as an important endocrine organ that plays a crucial role in energy metabolism and in the immune response in many metabolic tissues. With this regard, emerging evidence indicates that an important crosstalk exists between the adipose tissue and the brain. However, the contribution of adipose tissue to the development of age‐related diseases, including Alzheimer's disease, remains poorly defined. New studies suggest that the adipose tissue modulates brain function through a range of endogenous biologically active factors known as adipokines, which can cross the blood–brain barrier to reach the target areas in the brain or to regulate the function of the blood–brain barrier. In this review, we discuss the effects of several adipokines on the physiology of the blood–brain barrier, their contribution to the development of Alzheimer's disease and their therapeutic potential.LINKED ARTICLES: This article is part of a themed issue From Alzheimer's Disease to Vascular Dementia: Different Roads Leading to Cognitive Decline. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v181.6/issuetoc

Alzheimer´s disease (AD) is a complex neurodegenerative disorder that affects mainly the elder population. To date, modifying therapies have not proven to be successful, and therefore, a major effort is necessary to unravel the pathogenic processes underlying AD. New evidences indicate that AD and many other neurodegenerative diseases have commonly the accumulation of misfolded proteins that have the potential to act as infectious agents, and propagate through the entire brain, affecting native proteins. The amyloid peptide (Aβ), characteristic of AD, can adopt a β-sheet conformation acquiring the potential to aggregate and generate misfolded intermediates that can act as ‘’seeds’’ to propagate disease in the brain. Recent findings suggest that these seeds are structurally different depending on the patients and AD subtype, showing different propagation capacity and toxicity. In order to find out which Aβ species or isoforms are more toxic and have greater potential to aggregate, brain extracts from AD patients have been inoculated into transgenic AD mice brains. These approaches have provided much information, however, most of the models contain one or multiple dominant mutations of familial AD cases. This is of great value to mimic the familial forms of the disease, but not the late onset AD (LOAD), which constitute the majority of the cases. Therefore, new animal models are urgently necessary to circumvent these limitations and properly dissect the pathogenic mechanisms of this common form of the disease. As such, a new humanized Aβ model, called hAβ-KI, that has been generated by UCI-MODEL AD center at California, recapitulates certain features of LOAD. This might represent a useful LOAD model to understand how Aβ spreads and favors the progression of the pathology in the brain, hopefully enabling the development of effective therapeutic interventions for AD.

Alzheimer’s disease (AD) constitutes the most prominent form of dementia among elderly individuals worldwide. Disease modeling using murine transgenic mice was first initiated thanks to the discovery of heritable mutations in amyloid precursor protein (APP) and presenilins (PS) genes. However, due to the repeated failure of translational applications from animal models to human patients, along with the recent advances in genetic susceptibility and our current understanding on disease biology, these models have evolved over time in an attempt to better reproduce the complexity of this devastating disease and improve their applicability. In this review, we provide a comprehensive overview about the major pathological elements of human AD (plaques, tauopathy, synaptic damage, neuronal death, neuroinflammation and glial dysfunction), discussing the knowledge that available mouse models have provided about the mechanisms underlying human disease. Moreover, we highlight the pros and cons of current models, and the revolution offered by the concomitant use of transgenic mice and omics technologies that may lead to a more rapid improvement of the present modeling battery.

Editorial: Metabolic Alterations in Neurodegenerative Disorders

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. In addition, when exon 14 encoding the Aβ sequence was flanked by loxP sites we show that Cre-mediated excision of exon 14 ablates hAβ expression, rescues cognition and reduces the formation of PAS granules.