Matrix disequilibrium in Alzheimer’s disease and conditions that increase Alzheimer’s disease risk

Abstract

Alzheimer’s Disease (AD) and related dementias are a leading cause of death globally and are predicted to increase in prevalence. Despite this expected increase in the prevalence of AD, we have yet to elucidate the causality of the neurodegeneration observed in AD and we lack effective therapeutics to combat the progressive neuronal loss. Throughout the past 30 years, several non-mutually exclusive hypotheses have arisen to explain the causative pathologies in AD: amyloid cascade, hyper-phosphorylated tau accumulation, cholinergic loss, chronic neuroinflammation, oxidative stress, and mitochondrial and cerebrovascular dysfunction. Published studies in this field have also focused on changes in neuronal extracellular matrix (ECM), which is critical to synaptic formation, function, and stability. Two of the greatest non-modifiable risk factors for development of AD (aside from autosomal dominant familial AD gene mutations) are aging and APOE status, and two of the greatest modifiable risk factors for AD and related dementias are untreated major depressive disorder (MDD) and obesity. Indeed, the risk of developing AD doubles for every 5 years after ≥ 65, and the APOE4 allele increases AD risk with the greatest risk in homozygous APOE4 carriers. In this review, we will describe mechanisms by which excess ECM accumulation may contribute to AD pathology and discuss pathological ECM alterations that occur in AD as well as conditions that increase the AD risk. We will discuss the relationship of AD risk factors to chronic central nervous system and peripheral inflammation and detail ECM changes that may follow. In addition, we will discuss recent data our lab has obtained on ECM components and effectors in APOE4/4 and APOE3/3 expressing murine brain lysates, as well as human cerebrospinal fluid (CSF) samples from APOE3 and APOE4 expressing AD individuals. We will describe the principal molecules that function in ECM turnover as well as abnormalities in these molecular systems that have been observed in AD. Finally, we will communicate therapeutic interventions that have the potential to modulate ECM deposition and turnover in vivo.

Short‐term exposure to HIV Tat induces glial activation and changes in perineuronal nets

“…One limitation of our study, however, is that it is focused on short-term exposure to Tat. Recent studies suggest that while acute inflammation may increase MMPs and reduce ECM accumulation, long term inflammation may instead upregulate ECM deposition in end organs including brain, liver and kidneys (reviewed in Amontree et al, 2023;Ulbrich et al, 2021). We therefore suggest that future studies also examine HIV relevant changes in PNNs in longer-term more indolent models.…”

The Role of Galectin-3 in Retinal Degeneration and Other Ocular Diseases: A Potential Novel Biomarker and Therapeutic Target

“…However, its mechanism has not been fully elucidated. In the brain, the progressive nerve injury after an ischemic insult is considered to be mainly due to the neuroinflammatory process, in which the production of dysfunctional cytokines shows up [105], and neurotrophin is considered to play a major role as well [106][107][108]. It has been found that after focal ischemia, Gal3 in microglia is significantly upregulated, which contributes to tissue reconstruction after ischemia [80,105].…”