The multiple mechanisms of amyloid deposition: The role of parkin

Abstract

Amyloid deposition is one of the central neuropathological abnormalities in Alzheimer disease (AD) but it also takes places in many neurodegenerative diseases such as prionic disorders, Huntington's disease (HD) and others. Up to very recently amyloid formation was considered a very slow process of deposition of an abnormal protein due to genetic abnormalities or post-translational modification of the deposited protein. Recent data suggest that the process of amyloidogenesis may be much more rapid in many cases and due to multiple mechanisms.We have found a mouse model of progressive neurodegeneration that resemble motor, behavioral and pathological hallmarks of parkinsonism and tauopathies, but surprisingly, also present amyloid deposits in brain and peripheral organs. Here we review some of these recent works which may provide new insight into the process of formation of amyloid and, perhaps, new ideas for its treatment.

Natural Cannabinoids Improve Dopamine Neurotransmission and Tau and Amyloid Pathology in a Mouse Model of Tauopathy

“…It combines several potential neuroprotective effects, such as the stimulation of both CB1 and CB2 receptors by THC with the antioxidant effects of CBD [24]. Sativex ® is therefore especially adequate for the study of neuroprotective effects of cannabinoids on PK −/− /Tau VLW mice, a complex model of tauopathy, which has been previously described [25] and which combines cerebral and peripheral deposition of amyloid with lesions of the hippocampus, substantia nigra, and lower motor neuron and resembles a multisystemic neurological disease such as frontotemporal dementia with parkinsonism and amyotrophy [25][26][27][28]. These mice have lower levels of c-terminal HSP70 interacting protein (CHIP-HSP70), involved in the proteosomal degradation of tau, increased oxidative stress, measured as depletion of glutathione which, added to lack of parkin, could trigger tau accumulation and amyloidogenesis.…”

“…PK −/− /Tau VLW mice provide a link between the two proteins more important for the pathogenesis of Alzheimer's disease [25][26][27][28].…”

Amyloidosis in Domestic Animals: Pathology, Pathogenesis, Gross and Microscopic Lesions and Clinical Findings

“…The amyloidosis which causes neurodegenerative disorders is almost always related to the intracerebral production of the pathogenic protein since most proteins, like immunoglobulins, do not cross the blood brain barrier. One exception may be the case of systemic amyloidosis related to transtiretin mutations, which produce peripheral neuropathy and cerebral changes in the white matter in some cases (Mena, 2009). Aβ-amyloid in the brain tissue of aged dogs showing signs of dementia forms a canine counterpart of senile dementia of the Alzheimer type (ccSDAT) in man.…”

“…4). The common ultra structure of amyloid proteins is made of some nonbranching, rigid fibrils, 7.5 to 10 nm wide and of variable length, which arrange themselves in anti-parallel sheets with β structure (Mena, 2009). Microscopically, amyloid is deposited extracellularily in various affected tissues.…”

Sensibilidad de biomarcadores en el líquido cefalorraquídeo en enfermedades neurodegenerativas

“…La presencia de beta-amiloide (BA) en el cerebro humano es un hecho central en la etiopatogenia de la EA, aunque su relación con el desarrollo de la sintomatología clínica no está todavía totalmente aclarada 4 . Es probable que la carga de BA cerebral tenga una relación fisiopatológica precipitante con el resto de las alteraciones neuropatológicas encontradas en la EA, tales como la formación de ovillos neurofibrilares intraneuronales, hilillos del neuropilo, disfunción sináptica, activación de la microglía y cambios vasculares 5 . Sin embargo, esta cascada amiloidogénica todavía se mueve en el terreno de la hipótesis 6 .…”