Novel Insights into Neurodegenerative Diseases

Neurodegenerative diseases, such as Alzheimer disease (AD), cortical Lewy body disease, frontotemporal lobar degeneration, and other Alzheimer disease–related dementias (ADRDs), are the scourge of modern societies worldwide. In the United States alone, AD and ADRDs are the sixth leading cause of death.¹ These diseases impose a tremendous financial, physical, and mental burden on individuals affected by these diseases and their caregivers. Although new therapeutics, such as lecanemab and donanemab, are showing promise for slowing the progress of Alzheimer disease, they are not a cure. Several factors have complicated the development of safe and effective therapies for not only AD, but also other ADRDs. First, proper diagnosis of these diseases can be complicated. We now realize that multiple neurodegenerative diseases frequently coexist in the same brain, a condition known as mixed dementia, making it difficult to assess the effectiveness of candidate treatments. Overlapping and gender-specific disease presentations can further complicate diagnoses. Second, our understanding of the mechanisms that initiate and promote the pathogenesis of neurodegenerative diseases is also incomplete and at times contradictory, which impedes the conceptual development of new therapeutic regimens. Last, the multifactorial nature and heterogeneity of neurodegenerative diseases, combined with a lack of animal models that properly recapitulate human disease, further complicates the development of new therapies. Nonetheless, there is hope. In recent years, our understanding of the mechanisms underlying the pathogenesis of AD and ADRDs has expanded rapidly, and these cumulative research endeavors are bringing novel candidate therapies to clinical trials. It is thus timely that this theme issue of The American Journal of Pathology focuses on recent advances in understanding the pathogenesis of neurodegenerative diseases and the quest to develop new diagnostic and therapeutic tools. In this issue, authors with a variety of perspectives present 11 review articles that explore animal models of neurodegenerative diseases, recent advances in our understanding of the pathogenesis and pathobiology of AD and ADRDs, and the development of novel therapeutic approaches.

Neurodegenerative diseases are caused by a progressive functional impairment and, ultimately, loss of neurons and glia in the brain and spinal cord, which leads to cognitive, behavioral, motor, and other disabilities. Despite the fact that the pathology of AD and each of the ADRDs differs (and, indeed, these diseases are distinguished by their distinctive clinical and pathologic presentations), our growing understanding of the genetic and molecular abnormalities driving the pathogenesis of AD and ADRDs has made it clear that certain abnormalities are common to multiple neurodegenerative diseases.² These abnormalities include aberrant proteostasis, the development of pathologic protein aggregates, synaptic and neuronal network dysfunction, cytoskeletal abnormalities, altered energy metabolism, DNA and RNA defects, inflammation, and neuronal cell death. In keeping with this, several articles in this theme issue focus on one or more of these shared abnormalities.

Accumulation of abnormal proteinaceous material is the hallmark of a major subset of neurodegenerative diseases known as proteinopathies. Alzheimer disease, frontotemporal lobar degenerations, Parkinson disease, Huntington disease, and amyotrophic lateral sclerosis are well-known proteinopathies that are in dire need of relevant model systems and therapeutic treatments. In these diseases, the formation and accumulation of protein aggregates in the brain impairs neuronal health, which results in cognitive, motor, and other clinical abnormalities. Two reviews in this thematic issue focus on the therapeutic potential and controversial role of two notable aggregation-prone proteins, phosphorylated tau and amyloid β. Djurovic-Topalovic et al³ discuss therapeutic approaches focused on treating the disease, rather than the symptoms, by targeting novel tau-related proteins. Castellani et al⁴ provide clinical trial updates on the efficacy of targeting amyloid β as a treatment for sporadic AD. The role of amyloid β in the initiation and progression of AD is still controversial, in some investigators' opinion. By analyzing controlled clinical data, these authors provide novel insights that challenge the amyloid cascade theory. Protein misfolding and aggregation of monomers and oligomers disrupt protein homeostasis, which reflects a failed proteostasis network. Dysfunctional proteostasis is central to the development of these aggregates and the progression of both genetic and age-related causes of proteinopathies. Pytel and Fromm Longo⁵ describe the functional and molecular components of the proteostasis network and provide updates regarding the multifactorial and interconnecting drivers of proteinopathies. These authors also discuss therapeutic and nontherapeutic approaches to targeting proteostasis and the possibility that these interventions may be an effective means of treating proteinopathies.

Some of the abnormalities common to multiple neurodegenerative diseases, such as synaptic and neuronal network dysfunction, are thought to result from aberrant signaling by neurotrophic factors. A mechanistic review by Turner-Ivey et al⁶ highlights the specific role of wild-type and mutant erb-b2-receptor tyrosine kinase (ERBB)–related signaling in the development of Alzheimer disease, frontotemporal lobar degenerations, and amyotrophic lateral sclerosis. They describe how mechanistic diversity is achieved in neurons and glia via structural diversity of the ERBB ligands, which are known as neuregulins, and heterodimerization of the ERBB receptors. The role that disease-specific mutations in ERBB4 play in neuronal health and disease is discussed in detail for frontotemporal lobar degeneration and amyotrophic lateral sclerosis. These authors also discuss attempts to use neuregulins to treat these diseases.

Both proteinopathies and other neurodegenerative diseases have heterogeneous trajectories that are complicated by alterations in complex multicellular neuronal networks. Szczupak et al⁷ focus on evolving methods that are used to understand neuronal connectivity and cognitive resilience in the context of intercellular networks and maladaptive processes that cause system collapse and neurodegeneration. The disruption of neuronal networks in Alzheimer, Parkinson, and Huntington diseases is highlighted.

Not all neurodegenerative diseases are the result of defects intrinsic to neurons and, even for the diseases where neuronal abnormalities play an important role, factors extrinsic to neurons also contribute to the development of pathology. Four reviews by Babcock et al,⁸ Bearer,⁹ Mayer and Fischer,¹⁰ and Torre et al¹¹ highlight the role that factors extrinsic to neurons and environmental exposures potentially play in the development of neurodegenerative diseases. Babcock et al⁸ focus on the pathogenesis of chronic traumatic encephalopathy and its associated clinical symptoms, which are known as traumatic encephalopathy syndrome. These authors discuss the characteristic pathology of chronic traumatic encephalopathy, the biomechanics of repeated head impacts, and how these impacts affect the brain. They also explain the role that repetitive impacts play in both increasing the deposition of several pathologic proteins and predisposition to the development of Alzheimer disease and other neurodegenerative conditions. Bearer⁹ provides a detailed and well-considered review of cognitive impairment caused by vascular pathology, starting with a discussion of the anatomy of brain vasculature, the limitations of previous consensus guidelines for diagnosing vascular dementia pathology, and a scheme for categorizing vascular pathologies, including the appropriate stains for making these diagnoses. Bearer⁹ also considers the effects that microplastics and nanoplastics have on the brain and the function of the cerebral vasculature. Mayer and Fischer¹⁰ turn their attention to coronavirus disease 2019 (COVID-19) and the contributions that this virus likely makes to chronic neuroinflammation and disruption of the blood-brain barrier. These authors then consider the damage done by COVID-19, how that parallels the biochemical changes observed in Alzheimer disease, and the possibility that COVID-19 infection may be linked to the initiation and progression of Alzheimer disease. Torre et al¹¹ compare and contrast the cognitive impairment observed in Alzheimer disease and chemotherapy-related cognitive impairment and ask why more patients receiving chemotherapy do not develop Alzheimer disease, because these two conditions impact many of the same pathways.

Finally, the development of new tools for defining and understanding the pathogenesis of neurodegenerative diseases is critically important. In this issue, Julian et al¹² discuss new morphologic approaches to defining and diagnosing neurodegenerative diseases by combining whole slide imaging with advanced machine learning/artificial intelligence techniques. These authors also carefully consider the promise and challenges of these approaches and what will be necessary to move these techniques forward. Chiu et al¹³ consider the use of genetically engineered mice to model Alzheimer disease and frontotemporal dementia, focusing particularly on the exciting new findings that we are learning when single-cell transcriptomics, multiomics, and spatial transcriptomics are applied to these models. These authors critically assess these data, the new insights that the data have produced, and the limitations of using currently available mouse models for such studies.

As you can see, this theme issue contains varied approaches and perspectives to defining, understanding, and treating neurodegenerative diseases. We hope that these articles will spur new thinking and debate about how to approach these common, yet incredibly challenging, diseases.

Disclosure Statement

None declared.