HIPPOCAMPAL ASTROCYTES AND ALZHEIMER’S DISEASE

2014 ◽  
pp. 1-5
Author(s):  
J. Young
Keyword(s):  
Oxidative Stress ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Fatty Acid ◽  
Amyloid Precursor Protein ◽  
Precursor Protein ◽  
Fatty Acid Binding ◽  
Age Related ◽  
Mature Brain ◽  
Hippocampal Astrocytes

Considerable progress has been made in elucidating the molecules involved in the pathology of Alzheimer's disease (AD). However, it is still uncertain why the hippocampus is the focus of this pathology, since these molecules (amyloid precursor protein, beta secretase, apolipoprotein E) are not more abundant within the hippocampus than in other, undamaged brain areas. Several unique features of the hippocampus may make it more vulnerable to this age-related pathology. These include 1) a specialized metabolism that enhances damaging effects of oxidative stress, 2) a capacity for neurogenesis, and 3) specializations in mitochondrial and metal homeostasis. The thesis of this paper is that an unusual subset of hippocampal astrocytes makes a fundamental contribution to all three of these hippocampal features and allows different and seemingly conflicting risk factors for AD to be viewed in a unified manner. These astrocytes participate in neurogenesis, produce fatty acid binding protein 7, unlike most astrocytes in the mature brain, and undergo an age-related mitochondrial degeneration. Degeneration of astrocyte mitochondria appears due to oxidative stress arising from fatty acid metabolism. This mitochondrial degeneration produces intracellular deposits of iron and copper, metals that have been shown to harmfully interact with cleavage products of amyloid precursor protein. Pharmacological and dietary manipulations that protect these astrocytes from age-related oxidative stress may prove to be useful strategies in combatting the progression of AD.

scholarly journals SPON1 Can Reduce Amyloid Beta and Reverse Cognitive Impairment and Memory Dysfunction in Alzheimer’s Disease Mouse Model

Cells ◽  
2020 ◽  
Vol 9 (5) ◽  
pp. 1275
Author(s):  
Soo Yong Park ◽  
Joo Yeong Kang ◽  
Taehee Lee ◽  
Donggyu Nam ◽  
Chang-Jin Jeon ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Mouse Model ◽  
Amyloid Precursor Protein ◽  
Amyloid Beta ◽  
Physiological Activity ◽  
Precursor Protein ◽  
Age Related

Alzheimer’s disease (AD) is a complex, age-related neurodegenerative disease that is the most common form of dementia. However, the cure for AD has not yet been founded. The accumulation of amyloid beta (Aβ) is considered to be a hallmark of AD. Beta-site amyloid precursor protein cleaving enzyme 1 (BACE1), also known as beta secretase is the initiating enzyme in the amyloidogenic pathway. Blocking BACE1 could reduce the amount of Aβ, but this would also prohibit the other functions of BACE1 in brain physiological activity. SPONDIN1 (SPON1) is known to bind to the BACE1 binding site of the amyloid precursor protein (APP) and blocks the initiating amyloidogenesis. Here, we show the effect of SPON1 in Aβ reduction in vitro in neural cells and in an in vivo AD mouse model. We engineered mouse induced neural stem cells (iNSCs) to express Spon1. iNSCs harboring mouse Spon1 secreted SPON1 protein and reduced the quantity of Aβ when co-cultured with Aβ-secreting Neuro 2a cells. The human SPON1 gene itself also reduced Aβ in HEK 293T cells expressing the human APP transgene with AD-linked mutations through lentiviral-mediated delivery. We also demonstrated that injecting SPON1 reduced the amount of Aβ and ameliorated cognitive dysfunction and memory impairment in 5xFAD mice expressing human APP and PSEN1 transgenes with five AD-linked mutations.

scholarly journals Beta-Amyloid Precursor Protein (βAPP) Processing in Alzheimer’s Disease (AD) and Age-Related Macular Degeneration (AMD)

2014 ◽  
Vol 52 (1) ◽  
pp. 533-544 ◽  
Author(s):  
Yuhai Zhao ◽  
Surjyadipta Bhattacharjee ◽  
Brandon M. Jones ◽  
James M. Hill ◽  
Christian Clement ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Precursor Protein ◽  
Macular Degeneration ◽  
Beta Amyloid ◽  
Precursor Protein ◽  
Age Related Macular Degeneration ◽  
Age Related

scholarly journals β-Secretases, Alzheimer’s Disease, and Down Syndrome

2012 ◽  
Vol 2012 ◽  
pp. 1-8 ◽  
Author(s):  
Robin L. Webb ◽  
M. Paul Murphy
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Down Syndrome ◽  
Amyloid Precursor Protein ◽  
Healthy Aging ◽  
Precursor Protein ◽  
Chromosome 21 ◽  
Rate Limiting Step ◽  
Age Related

Individuals with Down Syndrome (DS), or trisomy 21, develop Alzheimer’s disease (AD) pathology by approximately 40 years of age. Chromosome 21 harbors several genes implicated in AD, including the amyloid precursor protein and one homologue of theβ-site APP cleaving enzyme, BACE2. Processing of the amyloid precursor protein byβ-secretase (BACE) is the rate-limiting step in the production of the pathogenic Aβpeptide. Increased amounts of APP in the DS brain result in increased amounts of Aβand extracellular plaque formation beginning early in life. BACE dysregulation potentially represents an overlapping biological mechanism with sporadic AD and a common therapeutic target. As the lifespan for those with DS continues to increase, age-related concerns such as obesity, depression, and AD are of growing concern. The ability to prevent or delay the progression of neurodegenerative diseases will promote healthy aging and improve quality of life for those with DS.

Cellular actions of beta-amyloid precursor protein and its soluble and fibrillogenic derivatives

1997 ◽  
Vol 77 (4) ◽  
pp. 1081-1132 ◽  
Author(s):  
M. P. Mattson
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Amyloid Precursor Protein ◽  
Amyloid Fibrils ◽  
Neuronal Excitability ◽  
Neuronal Degeneration ◽  
Beta Amyloid ◽  
Precursor Protein ◽  
Transport Systems ◽  
Age Related

beta-Amyloid precursor protein (beta-APP), the source of the fibrillogenic amyloid beta-peptide (A beta) that accumulates in the brain of victims of Alzheimer's disease, is a multifunctional protein that is widely expressed in the nervous system. beta-Amyloid precursor protein is axonally transported and accumulates in presynaptic terminals and growth cones. A secreted form of beta-APP (sAPP alpha) is released from neurons in response to electrical activity and may function in modulation of neuronal excitability, synaptic plasticity, neurite outgrowth, synaptogenesis, and cell survival. A signaling pathway involving guanosine 3',5'-cyclic monophosphate is activated by sAPP alpha and modulates the activities of potassium channels, N-methyl-D-aspartate receptors, and the transcription factor NF kappa B. Additional functions of beta-APP may include modulation of cell adhesion and regulation of proliferation of nonneuronal cells. Alternative enzymatic processing of beta-APP liberates A beta, which has a propensity to form amyloid fibrils; A beta can damage and kill neurons and increase their vulnerability to excitotoxicity. The mechanism involves generation of oxyradicals and impairment of membrane transport systems (e.g., ion-motive ATPases and glutamate and glucose transporters). Genetic mutations or age-related metabolic changes may promote neuronal degeneration in Alzheimer's disease by increasing production of A beta and/or decreasing levels of neuroprotective sAPP alpha.

Memapsin 2, a drug target for Alzheimer's disease

2003 ◽  
Vol 70 ◽  
pp. 213-220 ◽  
Author(s):  
Gerald Koelsch ◽  
Robert T. Turner ◽  
Lin Hong ◽  
Arun K. Ghosh ◽  
Jordan Tang
Keyword(s):  
Crystal Structure ◽  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Transition State ◽  
Amyloid Precursor Protein ◽  
Therapeutic Target ◽  
Drug Target ◽  
Aspartic Protease ◽  
Precursor Protein ◽  
Memapsin 2

Mempasin 2, a ϐ-secretase, is the membrane-anchored aspartic protease that initiates the cleavage of amyloid precursor protein leading to the production of ϐ-amyloid and the onset of Alzheimer's disease. Thus memapsin 2 is a major therapeutic target for the development of inhibitor drugs for the disease. Many biochemical tools, such as the specificity and crystal structure, have been established and have led to the design of potent and relatively small transition-state inhibitors. Although developing a clinically viable mempasin 2 inhibitor remains challenging, progress to date renders hope that memapsin 2 inhibitors may ultimately be useful for therapeutic reduction of ϐ-amyloid.

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