Viral gene transfer of APPsα rescues synaptic failure in an Alzheimer’s disease mouse model

Abstract Alzheimer’s disease (AD) is characterized by synaptic failure, dendritic and axonal atrophy, neuronal death and progressive loss of cognitive functions. It is commonly assumed that these deficits arise due to β-amyloid accumulation and plaque deposition. However, increasing evidence indicates that loss of physiological APP functions mediated predominantly by neurotrophic APPsα produced in the non-amyloidogenic α-secretase pathway may contribute to AD pathogenesis. Upregulation of APPsα production via induction of α-secretase might, however, be problematic as this may also affect substrates implicated in tumorigenesis. Here, we used a gene therapy approach to directly overexpress APPsα in the brain using AAV-mediated gene transfer and explored its potential to rescue structural, electrophysiological and behavioral deficits in APP/PS1∆E9 AD model mice. Sustained APPsα overexpression in aged mice with already preexisting pathology and amyloidosis restored synaptic plasticity and partially rescued spine density deficits. Importantly, AAV-APPsα treatment also resulted in a functional rescue of spatial reference memory in the Morris water maze. Moreover, we demonstrate a significant reduction of soluble Aβ species and plaque load. In addition, APPsα induced the recruitment of microglia with a ramified morphology into the vicinity of plaques and upregulated IDE and TREM2 expression suggesting enhance...
Source: Acta Neuropathologica - Category: Neurology Source Type: research

Related Links:

In conclusion, we show here that sEVs are responsible for mediating paracrine senescence and speculate that they could be involved in inducing bystander senescence during therapy-induced senescence or aging. In fact, when compared to soluble factors, sEVs have different biophysical and biochemical properties as they have a longer lifespan than do soluble factors and they are more resistant to protease degradation. The idea that blocking sEV secretion could be a potential therapeutic approach to alleviate senescence "spreading" during chemotherapy-induced senescence or in aging tissues presents itself as a very at...
Source: Fight Aging! - Category: Research Authors: Tags: Newsletters Source Type: blogs
In this study, we report the age-associated differences between fetal MSC (fMSC) populations and MSCs isolated from elderly donors with respect to their transcriptomes. We successfully reprogrammed fMSCs (55 days post conception) and adult MSC (aMSC; 60-74 years) to iPSCs and, subsequently, generated the corresponding iMSCs. In addition, iMSCs were also derived from ESCs. The iMSCs were similar although not identical to primary MSCs. We unraveled a putative rejuvenation and aging gene expression signature. We show that iMSCs irrespective of donor age and cell type re-acquired a similar secretome to that of th...
Source: Fight Aging! - Category: Research Authors: Tags: Newsletters Source Type: blogs
PAAND is a recently described monogenic auto-inflammatory disorder which shares clinical features with Familial Mediterranean Fever (FMF). PAAND unlike FMF, is not associated with serositis or amyloidosis. Although, different recessive and dominant mutations in MEFV can cause FMF, up to now, all reported cases of PAAND were associated with a dominant p.S242R mutation in MEFV. The proband was a 5-years old female born to healthy, consanguineous parents. She developed an oral aphthous ulcer at 20 days of age, followed by a maculo-papular and pustular skin rash on the perioral region and upper and lower extremities.
Source: Journal of Investigative Dermatology - Category: Dermatology Authors: Tags: Genetic Disease, Gene Regulation, and Gene Therapy Source Type: research
In conclusion, long-term aerobic exercise appears to attenuate the decline in endothelial vascular function, a benefit which is maintained during chronological aging. However, currently there is not enough evidence to suggest that exercise interventions improve vascular function in previously sedentary healthy older adults. Hijacking the Proteasome to Dispose of Unwanted Molecules in Age-Related Disease https://www.fightaging.org/archives/2019/03/hijacking-the-proteasome-to-dispose-of-unwanted-molecules-in-age-related-disease/ Cells are equipped with a protein disposal system in the form of the proteaso...
Source: Fight Aging! - Category: Research Authors: Tags: Newsletters Source Type: blogs
Klotho is a longevity gene in that more of the protein it codes for acts to modestly extend life in mice. Levels of klotho protein decline with age, and increased amounts appear to produce beneficial outcomes in health and longevity in part via stem cell function. Klotho also influences cognition, and a number of research groups are working on approaches, such as gene therapies to upregulate klotho expression, or delivery of recombinant protein fragments of the full klotho molecule, that might at some point result in ways to enhance cognitive function in humans, old and young alike. Klotho is known to be closely rel...
Source: Fight Aging! - Category: Research Authors: Tags: Daily News Source Type: blogs
Fight Aging! provides a weekly digest of news and commentary for thousands of subscribers interested in the latest longevity science: progress towards the medical control of aging in order to prevent age-related frailty, suffering, and disease, as well as improvements in the present understanding of what works and what doesn't work when it comes to extending healthy life. Expect to see summaries of recent advances in medical research, news from the scientific community, advocacy and fundraising initiatives to help speed work on the repair and reversal of aging, links to online resources, and much more. This content is...
Source: Fight Aging! - Category: Research Authors: Tags: Newsletters Source Type: blogs
AbstractRecent advances in pathophysiological and genetic mechanisms of some neuromuscular diseases and a rapid progress in new pharmacological technologies led to an accelerated development of innovative treatments, generating an unexpected therapeutic revolution. In part 1, we report already commercially available drugs, just approved drugs and new therapeutic promises in the treatment of peripheral neuropathies. Hereditary transthyretin amyloidosis (hATTR) is a devastating disease due to amyloid accumulation in peripheral nerves, heart and autonomic system. The first specific drug approved for hATTR was tafamidis, a TTR...
Source: Neurological Sciences - Category: Neurology Source Type: research
INTRODUCTION: Ig light chain (LC) diseases such as systemic AL amyloidosis (AL) and light chain deposition disease (LCDD) cause organ damage and are treated with chemotherapeutic agents targeting the clonal plasma cells producing the LC. Not all patients respond to therapy and responding patients remain at risk of relapse. New treatments are needed. In theory, alternative approaches that directly target LC for reduction include novel enzymatic agents (Infect Immun. 2003;71:2563), agents that retard LC monomerization (eLife. 2015;4:e10935. doi:10.7554), anti-light chain monoclonal antibodies (Blood 2004;104:2416), and small...
Source: Blood - Category: Hematology Authors: Tags: 652. Myeloma: Pathophysiology and Pre-Clinical Studies, excluding Therapy Source Type: research
In this report, we propose that the molecular mechanisms of beneficial actions of CR should be classified and discussed according to whether they operate under rich or insufficient energy resource conditions. Future studies of the molecular mechanisms of the beneficial actions of CR should also consider the extent to which the signals/factors involved contribute to the anti-oxidative, anti-inflammatory, anti-tumor and other CR actions in each tissue or organ, and thereby lead to anti-aging and prolongevity. RNA Interference of ATP Synthase Subunits Slows Aging in Nematodes https://www.fightaging.org/archives/...
Source: Fight Aging! - Category: Research Authors: Tags: Newsletters Source Type: blogs
Fight Aging! provides a weekly digest of news and commentary for thousands of subscribers interested in the latest longevity science: progress towards the medical control of aging in order to prevent age-related frailty, suffering, and disease, as well as improvements in the present understanding of what works and what doesn't work when it comes to extending healthy life. Expect to see summaries of recent advances in medical research, news from the scientific community, advocacy and fundraising initiatives to help speed work on the repair and reversal of aging, links to online resources, and much more. This content is...
Source: Fight Aging! - Category: Research Authors: Tags: Newsletters Source Type: blogs
More News: Amyloidosis | Brain | Gene Therapy | Genetics | Neurology | Pathology