g(m1)-ganglioside and Cerebral-Amyloid-Angiopathy

A major characteristic of Alzheimer's disease (AD) is the accumulation of misfolded amyloid-β (Aβ) peptide. Several studies linked AD with type 2 diabetes due to similarities between Aβ and human amylin. This study investigates the effect of amylin and pramlintide on Aβ pathogenesis and the predisposing molecular mechanism(s) behind the observed effects in TgSwDI mouse, a cerebral amyloid angiopathy (CAA) and AD model. Our findings showed that thirty days of intraperitoneal injection with amylin or pramlintide increased Aβ burden in mice brains. Mechanistic studies revealed both peptides altered the amyloidogenic pathway and increased Aβ production by modulating amyloid precursor protein (APP) and γ-secretase levels in lipid rafts. In addition, both peptides increased levels of B4GALNT1 enzyme and GM1 ganglioside, and only pramlintide increased the level of GM2 ganglioside. Increased levels of GM1 and GM2 gangliosides play an important role in regulating amyloidogenic pathway proteins in lipid rafts. Increased brain Aβ burden by amylin and pramlintide was associated with synaptic loss, apoptosis, and microglia activation. In conclusion, our findings showed amylin or pramlintide increase Aβ levels and related pathology in TgSwDI mice brains, and suggest that increased amylin levels or the therapeutic use of pramlintide could increase the risk of AD.

Topics: Alzheimer Disease; Amyloid beta-Protein Precursor; Amyloid Precursor Protein Secretases; Animals; Cerebral Amyloid Angiopathy; G(M1) Ganglioside; G(M2) Ganglioside; Islet Amyloid Polypeptide; Membrane Microdomains; Mice; Mice, Transgenic; N-Acetylgalactosaminyltransferases; Protein Processing, Post-Translational

Growing evidence suggests that diabetes mellitus (DM) is one of the strongest risk factors for developing Alzheimer's disease (AD). However, it remains unclear why DM accelerates AD pathology. In cynomolgus monkeys older than 25 years, senile plaques (SPs) are spontaneously and consistently observed in their brains, and neurofibrillary tangles are present at 32 years of age and older. In laboratory-housed monkeys, obesity is occasionally observed and frequently leads to development of type 2 DM. In the present study, we performed histopathological and biochemical analyses of brain tissue in cynomolgus monkeys with type 2 DM to clarify the relationship between DM and AD pathology. Here, we provide the evidence that DM accelerates Aβ pathology in vivo in nonhuman primates who had not undergone any genetic manipulation. In DM-affected monkey brains, SPs were observed in frontal and temporal lobe cortices, even in monkeys younger than 20 years. Biochemical analyses of brain revealed that the amount of GM1-ganglioside-bound Aβ (GAβ)--the endogenous seed for Aβ fibril formation in the brain--was clearly elevated in DM-affected monkeys. Furthermore, the level of Rab GTPases was also significantly increased in the brains of adult monkeys with DM, almost to the same levels as in aged monkeys. Intraneuronal accumulation of enlarged endosomes was also observed in DM-affected monkeys, suggesting that exacerbated endocytic disturbance may underlie the acceleration of Aβ pathology due to DM.

Topics: Age Factors; Alzheimer Disease; Amyloid beta-Peptides; Amyloidosis; Animals; Brain; Cathepsin D; Cerebral Amyloid Angiopathy; Diabetes Mellitus; Diabetes Mellitus, Type 2; Disease Models, Animal; Endocytosis; Female; G(M1) Ganglioside; Immunohistochemistry; Macaca fascicularis; Phagosomes; Plaque, Amyloid; rab GTP-Binding Proteins

Gangliosides, GM3 and GM1, are suggested to accelerate the deposition of the amyloid beta-protein as amyloid angiopathy and senile plaques, respectively, in the Alzheimer brain. We investigated the profile of amyloid deposition in the brains of transgenic mice expressing a mutant amyloid precursor protein with a disrupted GM2 synthase gene, in which GM3 accumulates whereas GM1 is lacking. These mice showed a significantly increased level of deposited amyloid beta-protein in the vascular tissues. Furthermore, formation of severe dyshoric-form amyloid angiopathy, in which amyloid extended from the blood vessel walls deeply into the surrounding parenchyma was observed. Our results indicate that the expression of gangliosides is a critical determinant for the amyloid pathology in the Alzheimer brain.

Topics: Aging; Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Blood Vessels; Blotting, Western; Brain; Cerebral Amyloid Angiopathy; G(M1) Ganglioside; G(M3) Ganglioside; Humans; Immunohistochemistry; Mice; Mice, Transgenic; Mutation; N-Acetylgalactosaminyltransferases; Protease Nexins; Receptors, Cell Surface