Alzheimer’s disease (AD) is the most frequent cause of age-related neurodegeneration and cognitive impairment, and there are currently no broadly effective therapies. The underlying pathogenesis is complex, but a growing body of evidence implicates mitochondrial dysfunction as a common pathomechanism involved in many of the hallmark features of the AD brain, such as formation of amyloid-beta (Aβ) aggregates (amyloid plaques), neurofibrillary tangles, cholinergic system dysfunction, impaired synaptic transmission and plasticity, oxidative stress, and neuroinflammation, that lead to neurodegeneration and cognitive dysfunction. Indeed, mitochondrial dysfunction concomitant with progressive accumulation of mitochondrial Aβ is an early event in AD pathogenesis. Healthy mitochondria are critical for providing sufficient energy to maintain endogenous neuroprotective and reparative mechanisms, while disturbances in mitochondrial function, motility, fission, and fusion lead to neuronal malfunction and degeneration associated with excess free radical production and reduced intracellular calcium buffering. In addition, mitochondrial dysfunction can contribute to amyloid-β precursor protein (APP) expression and misprocessing to produce pathogenic fragments (e.g., Aβ1-40). Given this background, we present an overview of the importance of mitochondria for maintenance of neuronal function and how mitochondrial dysfunction acts as a driver of cognitive impairment in AD. Additionally, we provide a brief summary of possible treatments targeting mitochondrial dysfunction as therapeutic approaches for AD.

Upregulation of reactive oxygen species (ROS) levels is a principal feature observed in the brains of neurodegenerative diseases such as Parkinson’s disease (PD) and Alzheimer’s disease (AD). In these diseases, oxidative stress can disrupt the blood–brain barrier (BBB). This disruption allows neurotoxic plasma components, blood cells, and pathogens to enter the brain, leading to increased ROS production, mitochondrial dysfunction, and inflammation. Collectively, these factors result in protein modification, lipid peroxidation, DNA damage, and, ultimately, neural cell damage. In this review article, we present the mechanisms by which oxidative damage leads to BBB breakdown in brain diseases. Additionally, we summarize potential therapeutic approaches aimed at reducing oxidative damage that contributes to BBB disruption in neurodegenerative diseases.

The blood–brain barrier (BBB) is a crucial structure that maintains brain homeostasis by regulating the entry of molecules and cells from the bloodstream into the central nervous system (CNS). Neurodegenerative diseases such as Alzheimer’s and Parkinson’s disease, as well as ischemic stroke, compromise the integrity of the BBB. This leads to increased permeability and the infiltration of harmful substances, thereby accelerating neurodegeneration. In this review, we explore the mechanisms underlying BBB disruption, including oxidative stress, neuroinflammation, vascular dysfunction, and the loss of tight junction integrity, in patients with neurodegenerative diseases. We discuss how BBB breakdown contributes to neuroinflammation, neurotoxicity, and the abnormal accumulation of pathological proteins, all of which exacerbate neuronal damage and facilitate disease progression. Furthermore, we discuss potential therapeutic strategies aimed at preserving or restoring BBB function, such as anti-inflammatory treatments, antioxidant therapies, and approaches to enhance tight junction integrity. Given the central role of the BBB in neurodegeneration, maintaining its integrity represents a promising therapeutic approach to slow or prevent the progression of neurodegenerative diseases.

Parkinson’s disease (PD) is a neurodegenerative disorder characterized by both motor symptoms and non-motor features. A hallmark of PD is the misfolding and accumulation of alpha-synuclein (α-syn), which triggers neuroinflammation and drives neurodegeneration. Microglia, brain cells that play a central role in neuroinflammatory responses and help clear various unnecessary molecules within the brain, thus maintaining the brain’s internal environment, respond to α-syn through mechanisms involving inflammation, propagation, and clearance. This review delves into the complex interplay between α-syn and microglia, elucidating how these interactions drive PD pathogenesis. Furthermore, we discuss emerging therapeutic strategies targeting the α-syn–microglia axis, with a focus on modulating microglial functions to mitigate neuroinflammation, enhance clearance, and prevent α-syn propagation, emphasizing their potential to slow PD progression.

The blood–brain barrier (BBB) restricts entry of neurotoxic plasma components, blood cells, and pathogens into the brain, leading to proper neuronal functioning. BBB impairment leads to blood-borne protein infiltration such as prothrombin, thrombin, prothrombin kringle-2, fibrinogen, fibrin, and other harmful substances. Thus, microglial activation and release of pro-inflammatory mediators commence, resulting in neuronal damage and leading to impaired cognition via neuroinflammatory responses, which are important features observed in the brain of Alzheimer’s disease (AD) patients. Moreover, these blood-borne proteins cluster with the amyloid beta plaque in the brain, exacerbating microglial activation, neuroinflammation, tau phosphorylation, and oxidative stress. These mechanisms work in concert and reinforce each other, contributing to the typical pathological changes in AD in the brain. Therefore, the identification of blood-borne proteins and the mechanisms involved in microglial activation and neuroinflammatory damage can be a promising therapeutic strategy for AD prevention. In this article, we review the current knowledge regarding the mechanisms of microglial activation-mediated neuroinflammation caused by the influx of blood-borne proteins into the brain via BBB disruption. Subsequently, the mechanisms of drugs that inhibit blood-borne proteins, as a potential therapeutic approach for AD, along with the limitations and potential challenges of these approaches, are also summarized.

We recently reported that adeno-associated virus serotype 1-constitutively active Ras homolog enriched in brain [AAV1-Rheb(S16H)] transduction of hippocampal neurons could induce neuron-astroglia interactions in the rat hippocampus in vivo, resulting in neuroprotection. However, it remains uncertain whether AAV1-Rheb(S16H) transduction induces neurotrophic effects and preserves the cognitive memory in an animal model of Alzheimer’s disease (AD) with characteristic phenotypic features, such as β-amyloid (Aβ) accumulation and cognitive impairments. To assess the therapeutic potential of Rheb(S16H) in AD, we have examined the beneficial effects of AAV1-Rheb(S16H) administration in the 5XFAD mouse model. Rheb(S16H) transduction of hippocampal neurons in the 5XFAD mice increased the levels of neurotrophic signaling molecules, including brain-derived neurotrophic factor (BDNF) and ciliary neurotrophic factor (CNTF), and their corresponding receptors, tropomyosin receptor kinase B (TrkB) and CNTF receptor α subunit (CNTFRα), respectively. In addition, Rheb(S16H) transduction inhibited Aβ production and accumulation in the hippocampus of 5XFAD mice and protected the decline of long-term potentiation (LTP), resulting in the prevention of cognitive impairments, which was demonstrated using novel object recognition testing. These results indicate that Rheb(S16H) transduction of hippocampal neurons may have therapeutic potential in AD by inhibiting Aβ accumulation and preserving LTP associated with cognitive memory.