Abstract
Alzheimer’s disease (AD) is a chronic neurodegenerative disorder and the leading cause of dementia. The disease progression is associated with the build-up of amyloid plaques and neurofibrillary tangles in the brain. However, besides the well-defined lesions, the AD-related pathology includes neuroinflammation, compromised energy metabolism, and chronic oxidative stress. Likewise, the blood–brain barrier (BBB) dysfunction is suggested to be a cause and AD consequence. Accordingly, therapeutic targeting of the compromised BBB is a promising disease-modifying approach. We utilized a homozygous triple-transgenic mouse model of AD (3×Tg-AD) to assess the effects of L-norvaline on BBB integrity. We scrutinized the perivascular astrocytes and macrophages by measuring the immunopositive profiles in relation to the presence of β-amyloid and compare the results with those found in wild-type animals. Typically, 3×Tg-AD mice display astroglia cytoskeletal atrophy, associated with the deposition of β-amyloid in the endothelia, and declining nitric oxide synthase (NOS) levels. L-norvaline escalated NOS levels, then reduced rates of BBB permeability, amyloid angiopathy, microgliosis, and astrodegeneration, which suggests AD treatment agent efficacy. Moreover, results undergird the roles of astrodegeneration and microgliosis in AD-associated BBB dysfunction and progressive cognitive impairment. L-norvaline self-evidently interferes with AD pathogenesis and presents a potent remedy for angiopathies and neurodegenerative disorders intervention.
Highlights
Alzheimer’s disease (AD) is an incurable chronic neurodegenerative disorder and the most common type of dementia [1]
We demonstrated that norvaline escalates the number of astrocytic processes in 3×Tg-AD mice (Figure 5E), which further supports the treatment-associated reversal of astrodegeneration in this model
We have sifted the evidence of L-norvaline neuroprotective properties with emphasis upon the blood–brain barrier (BBB) integrity in a murine model of AD
Summary
Alzheimer’s disease (AD) is an incurable chronic neurodegenerative disorder and the most common type of dementia [1]. The disease development is characterized by progressive brain atrophy, amyloid-beta (Aβ) deposition, and neurofibrillary tangles (NFT) formation throughout the brain parenchyma [2]. Despite a century-long investigation and recent significant evolution in our understanding of the disease pathogenesis, there is no complete scientific consensus concerning the causes of the disease, which seriously hinders the search for AD-modifying remedies. The Aβ peptides deposit extensively in the vessel walls, which causes cerebral amyloid angiopathy (CAA) [3]. A remarkable experiment applying in vivo imaging of CAA in seven-month-old AD mice by Kim et al (2015) demonstrated the Aβ deposits wrapped around the vessel wall in patches [4]. Other studies have shown prominent cerebral amyloid angiopathy in transgenic mice overexpressing human APP in neurons [5]
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