Converging on 9 Areas of Focus

Pathological Pathways and Systems


While some of our funded research projects have moved on to the stages of translational research and drug development, we continue to broaden our understanding of Alzheimer’s by funding additional research into the underlying causes and mechanisms of the disease. Projects in the Pathological Pathways and Systems category aim to elucidate the mechanisms by which the known pathologies of Alzheimer’s disease, such as Abeta accumulation, tau tangle propagation and inflammation, arise and progress, whether or not expression of a specific gene or genes has yet been identified as a root cause. 

 

 

Project Description Researchers
Tau Missorting in AD—Causes and Consequences

During the development of Alzheimer’s dementia, multiple changes occur in brain cells, making the search for and treatment of underlying causes difficult. Therefore, a key goal of Alzheimer’s disease (AD) research is to identify early changes occurring long before cognitive deficits become apparent. One such event is the so-called "missorting" of tau protein, which normally is found in the axons of neurons, but which in AD accumulates in the ''wrong'' compartments, the cell bodies and dendrites.

Propagation of Tauopathy and Ubiquitin Proteasome System Dysfunction: Impact and Rescue with a UPS Activator

The brain of a patient with Alzheimer’s disease shows two abnormalities: clumps of a protein called amyloid into what is known as amyloid plaques, and clumps of a protein called tau into what is known as neurofibrillary tangles. One of the features of Alzheimer’s disease is that the tangles start in one part of the brain (areas involved in memory and learning), but they infect new regions and spread through the brain, contributing to the worsening of the disease.

Genetic Targets to Block Tau Propagation: Test Knockdown of Heparan Sulfate Proteoglycan Genes In Vivo

Trans-cellular propagation of tau pathology has been implicated in the progression of Alzheimer’s disease and other tauopathies. We previously have determined the mechanism by which tau aggregates bind the cell surface to trigger uptake via macropinocytosis. This involves direct binding of tau to heparan sulfate proteoglycans (HSPGs) on the cell surface. HSPGs are glycolipid-anchored and transmembrane core proteins that are extensively glycosylated and sulfated by a defined set of cellular enzymes.

Early Role of Microglia in Synapse Loss in Alzheimer’s Disease

In Alzheimer’s disease (AD), synaptic connections are lost early and in specific areas of the brain, including the hippocampus, where memory is formed and stored; however, what makes synapses vulnerable in AD and other neurodegenerative diseases remains elusive. In the healthy developing brain, synaptic loss (also known as synaptic pruning) is a normal process required for proper brain development. We previously found a key role for a group of immune molecules called complement in synaptic pruning.

Inhibition of Tau Pathology in Human Neurons

The work proposed in this application stems from dramatic advances in our understanding of reasons that nerve cells die in Alzheimer’s disease. This work derives from new insights into how our bodies respond to stress. We have discovered a group of proteins, termed RNA-binding proteins (RBPs), that bind directly to tau protein (one of the major proteins that accumulates in the brains of patients with Alzheimer’s disease). Binding of these RBPs causes tau to form small clumps, termed oligomers, which are very harmful.

Uncovering Determinants of Neuronal Vulnerability in Alzheimer's Disease

Neurofibrillary tangles (NFTs) and neurodegeneration occur only in very specific regions at early stages of Alzheimer’s disease (AD), while many regions remain virtually unaffected. Using the bacTRAP technology the lab developed to isolate mRNAs from specific neuron types, we molecularly profiled these very vulnerable neurons and other neurons that are much more resistant to pathological lesions of AD. We looked for genes enriched in vulnerable neurons compared with resistant neurons, and were able to pinpoint a list of these candidate vulnerability genes.

Systemic Inflammatory Networks in Alzheimer's Disease

A common early symptom of Alzheimer’s disease (AD) is short-term memory loss. As the disease worsens, symptoms can include problems with language, disorientation, mood and behavior changes, confusion about events, difficulty speaking, swallowing and walking. AD is the most common form of dementia and worsens over time, accounting for approximately 70 percent of dementia cases. It is a neurodegenerative disease characterized by loss of normal brain function as a result of damage and destruction of nerve cells.

Understanding Reactive Astrocytes and Their Roles in Alzheimer’s Disease

We are investigating the mechanisms that cause neurodegeneration in Alzheimer’s disease. Our recent studies have led us to realize that a toxic protein is unexpectedly secreted by a class of brain cells called astrocytes in the setting of Alzheimer’s disease. Our goal in this proposal is to identify this protein so that, in future studies, we can test whether drugs that block the production or action of this protein will be useful as new therapies for Alzheimer’s disease.

Rejuvenation of Microglia in Brain Aging and Neurodegeneration

Aging impacts nearly every tissue and function in an organism, and the associated deterioration is the primary risk factor for major human diseases, including cancer, cardiac disease and such neurodegenerative diseases as Alzheimer’s disease. The underlying cause of aging is likely a multifaceted yet interconnected tangle of processes, but there is growing evidence that in the brain, microglia—which are the only resident immune cell—have a major role.

Cell Cycle Re-entry in 3-D Human Neuron Cultures

The well-known behavioral symptoms of Alzheimer’s disease (AD) are caused by the loss of connections, or synapses, among neurons that control memory and cognition, and by the death of those neurons. A major goal of our labs is to unravel the seminal molecular pathways that convert normal healthy neurons into neurons that will die long before the AD patients themselves.

Intersection of Microglial Transcriptomes to Identify Key Alzheimer’s Pathways of Brain Phagocytes

Computational analysis of gene expression profiles of moderate to severely affected Alzheimer’s disease (AD) patients (Zhang et al., Cell, 2013) indicates that DAP12/TYROBP is an important “hub” or “driver” for the pathogenesis of typical, late-onset, sporadic AD. This is the first genetic risk factor for this common form of the illness to be predicted by this new “big data” approach. Conveniently, this prediction dovetails well with a potent risk factor, TREM2, recently identified to be mutated in some patients with late-onset AD.

The Role of Meningeal Lymphatics in Cleansing the Brain: Implications for Alzheimer’s Disease

Blood vessels supply our organs with oxygen and nutrients. Another set of vessels, called the lymphatic vessels, perform other very important roles in the maintenance of tissues as they remove all the waste and toxic compounds the organ produces and also serve as a path for immune cells from organs back to the lymph nodes. The mammalian central nervous system (CNS) thus far has been considered one of the only organs devoid of lymphatic vessels, and it was not fully understood how toxic compounds are removed from the brain.

Role of Neurexins in Alzheimer’s Disease Pathophysiology

Pathogenesis of Alzheimer's disease (AD) is directly linked to levels of the toxic amyloid beta (Abeta) peptide in the brain. Abeta levels and amyloid deposition increase in aging and in AD, yet age-dependent factors that increase Abeta levels at the synapse remain largely unknown. In large family-based genome-wide association studies (GWAS), we recently have discovered a strong association between a neurexin gene and late-onset AD, and identified a number of neurexin variants that are associated with increased risk for AD.

Will Restoration of Normal Glymphatic Function Slow Progression of Cognitive Decline and Amyloid Plaques in a Murine Alzheimer Model?

This proposal will map glymphatic function as a function of aging in a mouse model of Alzheimer’s disease. We also will test the hypothesis that exercise and improved sleep can slow the progression of cognitive decline by improving glymphatic clearance.

Regulation of Microglial Lysosome Acidification

Microglia are the main immune cells of the central nervous system. They normally carry out diverse functions, including removal of dead cells and other debris from the brain. Under some circumstances they have been shown to degrade Alzheimer’s disease amyloid plaques in acidic organelles called lysosomes. We have shown that the acidity of microglial lysosomes is controlled by signaling processes, and that resting microglia in cell culture are ineffective at degrading amyloid because of poor lysosome acidification.

Optimization of Pharmacalogic Properties of Molecular Tweezers

Molecular tweezers (MTs) are compounds that act as Misfolded-Protein Clearance Enhancers (MPCEs) using a unique mechanism. They remodel the self-assembly of amyloidogenic proteins into formation of non-toxic and non-amyloidogenic structures that can be degraded efficiently by the natural clearance mechanisms. A lead MT called CLR01 has been found to prevent the self-assembly of multiple amyloid proteins into toxic oligomers and aggregates, including the proteins involved in Alzheimer’s disease (AD)—amyloid β-protein (Abeta) and tau.

Regulation of RNA Translation by MAPT in Alzheimer’s Disease

We have recently identified a new type of molecular pathology in AD that develops in concert with neurofibrillary tangles, which are one of the hallmark pathologies of Alzheimer’s disease (AD). Neurofibrillary tangles form from clumping of tau protein, and occur as nerve cells deteriorate. In the Wolozin lab, we have discovered that a class of proteins, termed RNA binding proteins, clump alongside the tau protein and constitute a new type of pathology in the AD.

Long Abetas, Intraneuronal Amyloid and an Alternative Amyloid Hypothesis of Alzheimer’s Disease

The goal of this proposal is to test a new paradigm for the causative mechanisms of Alzheimer’s disease (AD): The accumulation of amyloid aggregates inside neurons leading to their degeneration and initiating plaque formation. The hypothesis we will test is the inverse or mirror image of the commonly held view of the amyloid hypothesis of AD, which proposes that soluble Abeta is secreted from neurons, aggregates in the extracellular space and causes neuronal dysfunction from the outside.