Association of Retromer Deficiency and Tau Pathology in Down Syndrome.

Retromer deficiency is reported in Down syndrome and correlates with amyloidosis, however, its association with tau neuropathology remains unclear. Down syndrome and control brain tissues were evaluated for phosphorylated tau, tau modulators, and cathepsin-D activity. Several kinases and phosphatase PP2A were unchanged, but tau phosphorylation was elevated, and cathepsin-D activity decreased in aged patients with Down syndrome. Retromer proteins positively associated with soluble tau, whereas pathogenic tau negatively correlated with retromer proteins and cathepsin-D activity. Retromer deficiency and consequent reduction of cathepsin-D activity may contribute to pathogenic tau accumulation, thus, retromer represents a viable therapeutic target against tau pathology in Down syndrome. ANN NEUROL 2022;91:561-567.

Gestational high fat diet protects 3xTg offspring from memory impairments, synaptic dysfunction, and brain pathology.

Maternal history for sporadic Alzheimer's disease (AD) predisposes the offspring to the disease later in life. However, the mechanisms behind this phenomenon are still unknown. Lifestyle and nutrition can directly modulate susceptibility to AD. Herein we investigated whether gestational high fat diet influences the offspring susceptibility to AD later in life. Triple transgenic dams were administered high fat diet or regular chow throughout 3 weeks gestation. Offspring were fed regular chow throughout their life and tested for spatial learning and memory, brain amyloidosis, tau pathology, and synaptic function. Gestational high fat diet attenuated memory decline, synaptic dysfunction, amyloid-ß and tau neuropathology in the offspring by transcriptional regulation of BACE-1, CDK5, and tau gene expression via the upregulation of FOXP2 repressor. Gestational high fat diet protects offspring against the development of the AD phenotype. In utero dietary intervention could be implemented as preventative strategy against AD.

Dysregulation of the Retromer Complex System in Down Syndrome.

OBJECTIVE: Most of the patients with Down syndrome (DS) develop Alzheimer's disease (AD) neuropathology by age 40. Although this increased susceptibility to AD in DS is thought to be primarily due to triplication of the amyloid precursor protein located on chromosome 21, the precise molecular mechanisms are not well understood. Recent evidence has implicated defective protein sorting and trafficking secondary to deficiencies in retromer complex proteins in AD pathogenesis. Thus, the objective of the present study is to assess the retromer complex system in DS. METHODS: Human postmortem brain tissue and fibroblasts from subjects with DS and healthy controls were examined for the various retromer protein components using Western blot analysis and reverse transcription quantitative polymerase chain reaction (RT-qPCR). RESULTS: Retromer recognition core proteins were significantly decreased in DS fibroblasts, and in both the hippocampi and cortices of young (age 15-40 years old) and aged (40-65 years old) subjects with DS compared with controls. Correlation analyses showed a significant inverse relationship between recognition core proteins and levels of soluble forms of Aß 1-40 and 1-42 in both hippocampus (n = 33, Spearman = -0.59 to -0.38, p ≤ 0.03 for VPS35, VPS26, VPS29, and VPS26B) and cortex tissue (n = 57, Spearman = -0.46 to -0.27, p ≤ 0.04 for VPS35, VPS26, and VPS29) of the same patients. INTERPRETATION: We conclude that dysregulation of the retromer complex system is an early event in the development of the AD-like pathology and cognitive decline in DS, and for this reason the system could represent a novel potential therapeutic target for DS. ANN NEUROL 2020 ANN NEUROL 2020;88:137-147.

Retromer Stabilization Improves Cognitive Function and Synaptic Plasticity in a Mouse Model of Down Syndrome.

BACKGROUND: Retromer complex proteins are decreased in postmortem brain tissues from Down syndrome subjects and inversely correlate with the Alzheimer's disease-like neuropathology. However, whether targeting in vivo the retromer system affects cognitive deficits and synaptic function in Down syndrome remains unknown. OBJECTIVE: The aim of the current study was to examine the effects of pharmacological retromer stabilization on cognitive and synaptic functions in a mouse model of Down syndrome. METHODS: Ts65dn mice were administered the pharmacological chaperone, TPT-172, or vehicle from 4 to 9 months of age and then assessed for changes in cognitive function. To assess the effects of TPT-172 on synaptic plasticity, hippocampal slices from Ts65dn mice were incubated in TPT-172 and used for field potential recordings. RESULTS: Chronic TPT-172 treatment improved performance in cognitive function tests, its incubation with hippocampal slices ameliorated synaptic function response. CONCLUSION: Pharmacological stabilization of the retromer complex improves synaptic plasticity and memory in a mouse model of Down syndrome. These results support the therapeutic potential of pharmacological retromer stabilization for individual with Down syndrome.

Dysfunction of the retromer complex system contributes to amyloid and tau pathology in a stem cell model of Down syndrome.

Introduction: Retromer complex proteins are decreased in Down syndrome (DS) brains and correlate inversely with brain amyloidosis. However, whether retromer dysfunction contributes to the amyloid beta (Aß) and tau neuropathology of DS remains unknown. Methods: Human trisomic induced Pluripotent Stem Cells (iPSCs) and isogenic controls were differentiated into forebrain neurons, and changes in retromer proteins, tau phosphorylated epitopes, and Aß levels were assessed in euploid and trisomic neurons using western blot and enzyme-linked immunosorbent assay (ELISA). Genetic overexpression and pharmacological retromer stabilization were used to determine the functional role of the retromer complex system in modulating amyloid and tau pathology. Results: Trisomic neurons developed age-dependent retromer core protein deficiency associated with accumulation of Aß peptides and phosphorylated tau isoforms. Enhancing retromer function through overexpression or pharmacological retromer stabilization reduced amyloid and tau pathology in trisomic neurons. However, the effect was greater using a pharmacological approach, suggesting that targeting the complex stability may be more effective in addressing this neuropathology in DS. Discussion: Our results demonstrate that the retromer complex is directly involved in the development of the neuropathologic phenotype in DS, and that pharmacological stabilization of the complex should be considered as a novel therapeutic tool in people with DS.

Autophagy Dysfunction in Alzheimer's Disease: Mechanistic Insights and New Therapeutic Opportunities.

Alzheimer's disease (AD) is a neurodegenerative disorder characterized by progressive memory loss due to aberrant accumulation of misfolded proteins inside and outside neurons and glial cells, leading to a loss of cellular protein homeostasis. Today, no therapy is available to block or slow down AD progression, and the mechanisms of the disease are not fully understood. Autophagy is an intracellular degradation pathway crucial to maintaining cellular homeostasis by clearing damaged organelles, pathogens, and unwanted protein aggregates. In recent years, autophagy dysfunction has gained considerable attention in AD and other neurodegenerative diseases because it has been linked to the accumulation of misfolded proteins that ultimately causes neuronal death in many of these disorders. Interestingly, autophagy-activating compounds have also shown some promising results in both clinical trials and preclinical studies. This review aims at summarizing the current knowledge on autophagy dysfunction in the context of AD pathophysiology, providing recent mechanistic insights on AD-mediated autophagic flux disruption and highlighting potential and novel therapeutic opportunities that target this system for AD therapy.