Insurmountable evidence has demonstrated a strong association between Alzheimer's disease (AD) and cerebral amyloid angiopathy (CAA), along with various other cerebrovascular diseases. One form of ...CAA, which is the accumulation of amyloid-beta peptides (Aβ) along cerebral vessel walls, impairs perivascular drainage pathways and contributes to cerebrovascular dysfunction in AD. To date, CAA research has been primarily focused on arterial Aβ, while the accumulation of Aβ in veins and venules were to a lesser extent. In this review, we describe preclinical models and clinical studies supporting the presence of venular amyloid and potential downstream pathological mechanisms that affect the cerebrovasculature in AD. Venous collagenosis, impaired cerebrovascular pulsatility, and enlarged perivascular spaces are exacerbated by venular amyloid and increase Aβ deposition, potentially through impaired perivascular clearance. Gaining a comprehensive understanding of the mechanisms involved in venular Aβ deposition and associated pathologies will give insight to how CAA contributes to AD and its association with AD-related cerebrovascular disease. Lastly, we suggest that special consideration should be made to develop Aβ-targeted therapeutics that remove vascular amyloid and address cerebrovascular dysfunction in AD.
Patient-to-patient variability in the degree to which β-amyloid, tau and neurodegeneration impact cognitive decline in Alzheimer's disease (AD) complicates disease modeling and treatment. However, ...the underlying mechanisms leading to cognitive resilience are not resolved. We hypothesize that the variability in cognitive function and loss relates to neuronal resilience of the hippocampal GABAergic network.
We compared TgF344-AD and non-transgenic littermate rats at 9, 12, and 15 months of age. Neurons, β-amyloid plaques and tau inclusions were quantified in hippocampus and entorhinal cortex. Somatostatin (SST) and parvalbumin (PVB) interneurons were traced to examine hippocampal neuroplasticity and cognition was tested in the Barnes maze.
The 9-month-old TgF344-AD rats exhibited loss of neurons in the entorhinal cortex and hippocampus. Hippocampal neuronal compensation was observed in 12-month TgF344-AD rats, with upregulation of GABAergic interneuronal marker. By 15 months, the TgF344-AD rats had robust loss of excitatory and inhibitory neurons. β-Amyloid and tau pathology accumulated continuously across age. SST interneurons exhibited tau inclusions and atrophy from 9 months, whereas PVB interneurons were resilient until 15 months. The hippocampal PVB circuit underwent neuroplastic reorganization with increased dendritic length and complexity in 9- and 12-month-old TgF344-AD rats, before atrophy at 15 months. Strikingly, 12-month-old TgF344-AD rats were resilient in executive function and cognitive flexibility. Cognitive resilience in TgF344-AD rats occurred as maintenance of function between 9 and 12 months of age despite progressive spatial memory deficits, and was sustained by PVB neuroplasticity.
Our results demonstrate the inherent neuronal processes leading to cognitive maintenance, and describe a novel finding of endogenous cognitive resilience in an AD model.
The adoption of CRISPR-Cas9 technology for functional genetic screens has been a transformative advance. Due to its modular nature, this technology can be customized to address a myriad of questions. ...To date, pooled, genome-scale studies have uncovered genes responsible for survival, proliferation, drug resistance, viral susceptibility, and many other functions. The technology has even been applied to the functional interrogation of the non-coding genome. However, applications of this technology to neurological diseases remain scarce. This shortfall motivated the assembly of a review that will hopefully help researchers moving in this direction find their footing. The emphasis here will be on design considerations and concepts underlying this methodology. We will highlight groundbreaking studies in the CRISPR-Cas9 functional genetics field and discuss strengths and limitations of this technology for neurological disease applications. Finally, we will provide practical guidance on navigating the many choices that need to be made when implementing a CRISPR-Cas9 functional genetic screen for the study of neurological diseases.
In Alzheimer’s disease (AD), Aβ is deposited along the brain parenchyma as well as the cerebral blood vessels, a pathology named cerebral amyloid angiopathy (CAA). Currently, research has expanded on ...arteriolar CAA, while venular amyloid deposition have yet to be fully explained. My objective is to understand venular amyloid by identifying the Aβ peptide and studying the interplay between venular amyloid and CAA deposition. Mass spectrometry (MS) analysis of amyloid deposits isolated from TgF344-AD rat brains using laser capture microdissection (LCM) identified low abundance Aβ in venular amyloid. In addition, histopathological analysis demonstrated severe arteriolar amyloid accumulation preceding venular amyloid deposition. Immunofluorescent imaging confirmed localization of vascular Aβ along the perivascular spaces of arteries and veins, suggesting perivascular drainage impairments leading to CAA and venular amyloid. Gaining a comprehensive understanding of the mechanisms involved in venular Aβ deposition and associated pathologies provides insight to the connection between CAA and AD.
Abstract
Background
In Alzheimer’s Disease (AD), the amyloid‐beta peptide (Aβ) aggregates and deposits in the form of amyloid plaques within the brain parenchyma. Overproduction of Aβ is less common ...in sporadic AD cases, suggesting that impairment in Aβ clearance contributes to disease pathology. In AD, failure of the perivascular drainage pathway leads to Aβ deposition in the walls of cerebral blood vessels, resulting in cerebral amyloid angiopathy (CAA). The association between amyloid deposits with arterioles and capillaries is known, however, amyloid deposits present in venules is still controversial.
Method
A TgF344‐AD rat model overexpressing the human APPswe and PS1ΔE9 mutations was used as it recapitulates the typical hallmarks of AD in humans, including Aβ plaque formation, CAA, tau pathology, frank neuronal loss, and cognitive deficits. At 7, 10, 13, and 16 months of age, brain sections were examined by immunofluorescence staining and image analyses for amyloid deposits around all blood vessels using Thioflavin S staining. Further identification of deposits with Aβ specific antibodies, 4G8 (17‐28), MOAB2 (1‐4), and anti‐Aβ1‐40/42, were used to confirm Thioflavin results. Amyloid aggregates were isolated from parenchymal plaques, CAA, and venular amyloid using a laser capture microdissection (LCM) microscope and sent for mass‐spectrometry (MS) to identify the presence of Aβ.
Result
Results suggest as an increase in CAA is detected, venular amyloid starts to accumulate, with disease progression. Confirmation with antibodies that span the Aβ sequence, 4G8, MOAB2, anti‐Aβ1‐40/42, identify amyloid deposits in both venules and arterioles. Furthermore, LCM‐MS technique identified presence of Aβ in cortical plaques and CAA samples.
Conclusion
Correlation with venular amyloid deposition and CAA suggests an important interplay between these vascular pathologies with AD progression. Understanding venular amyloid and its relationship with CAA can play a role in studying mechanisms involved in neurovascular dysfunction of AD.
Background
In Alzheimer’s Disease (AD), the amyloid‐beta peptide (Aβ) aggregates and deposits in the form of amyloid plaques within the brain parenchyma. Overproduction of Aβ is less common in ...sporadic AD cases, suggesting that impairment in Aβ clearance contributes to disease pathology. In AD, failure of the perivascular drainage pathway leads to Aβ deposition in the walls of cerebral blood vessels, resulting in cerebral amyloid angiopathy (CAA). The association between amyloid deposits with arterioles and capillaries is known, however, amyloid deposits present in venules is still controversial.
Method
A TgF344‐AD rat model overexpressing the human APPswe and PS1ΔE9 mutations was used as it recapitulates the typical hallmarks of AD in humans, including Aβ plaque formation, CAA, tau pathology, frank neuronal loss, and cognitive deficits. At 7, 10, 13, and 16 months of age, brain sections were examined by immunofluorescence staining and image analyses for amyloid deposits around all blood vessels using Thioflavin S staining. Further identification of deposits with Aβ specific antibodies, 4G8 (17‐28), MOAB2 (1‐4), and anti‐Aβ1‐40/42, were used to confirm Thioflavin results. Amyloid aggregates were isolated from parenchymal plaques, CAA, and venular amyloid using a laser capture microdissection (LCM) microscope and sent for mass‐spectrometry (MS) to identify the presence of Aβ.
Result
Results suggest as an increase in CAA is detected, venular amyloid starts to accumulate, with disease progression. Confirmation with antibodies that span the Aβ sequence, 4G8, MOAB2, anti‐Aβ1‐40/42, identify amyloid deposits in both venules and arterioles. Furthermore, LCM‐MS technique identified presence of Aβ in cortical plaques and CAA samples.
Conclusion
Correlation with venular amyloid deposition and CAA suggests an important interplay between these vascular pathologies with AD progression. Understanding venular amyloid and its relationship with CAA can play a role in studying mechanisms involved in neurovascular dysfunction of AD.
Traumatic brain injury (TBI) research has focused on moderate to severe injuries as their outcomes are significantly worse than those of a mild TBI (mTBI). However, recent epidemiological evidence ...has indicated that a series of even mild TBIs greatly increases the risk of neurodegenerative and psychiatric disorders. Neuropathological studies of repeated TBI have identified changes in neuronal ionic concentrations, axonal injury, and cytoskeletal damage as important determinants of later life neurological and mood compromise; yet, there is a paucity of data on the contribution of neurogliovascular dysfunction to the progression of repeated TBI and alterations of brain function in the intervening period.
Here, we established a mouse model of repeated TBI induced via three electromagnetically actuated impacts delivered to the intact skull at three-day intervals and determined the long-term deficits in neurogliovascular functioning in Thy1-ChR2 mice. Two weeks post the third impact, cerebral blood flow and cerebrovascular reactivity were measured with arterial spin labelling magnetic resonance imaging. Neuronal function was investigated through bilateral intracranial electrophysiological responses to optogenetic photostimulation. Vascular density of the site of impacts was measured with in vivo two photon fluorescence microscopy. Pathological analysis of neuronal survival and astrogliosis was performed via NeuN and GFAP immunofluorescence.
Cerebral blood flow and cerebrovascular reactivity were decreased by 50±16% and 70±20%, respectively, in the TBI cohort relative to sham-treated animals. Concomitantly, electrophysiological recordings revealed a 97±1% attenuation in peri-contusional neuronal reactivity relative to sham. Peri-contusional vascular volume was increased by 33±2% relative to sham-treated mice. Pathological analysis of the peri-contusional cortex demonstrated astrogliosis, but no changes in neuronal survival.
This work provides the first
characterization of the long-term deficits of the neurogliovascular unit following repeated TBI. The findings will help guide the development of diagnostic markers as well as therapeutics targeting neurogliovascular dysfunction.
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