Alzheimers disease

Alzheimer's disease (AD), together with multi-infarct dementia, is the main cause of senile dementia. AD, named after Alois Alzheimer, who was the first to describe this pathology in 1907, is characterized by profound neuronal loss throughout the brain which rapidly compromises memory and results in severe impairment of cognitive functions. Histological hallmarks of AD are represented by the formation of deposits of ß-amyloid protein (Aß) in the walls of blood vessels, accumulation of Aß plaques in the grey matter and intra-neuronal accumulation of abnormal tau-protein filaments in the form of neuronal tangles. AD is also characterized by prominent reactive astrogliosis and activation of microglia (incidentally, the involvement of glial cells in pathogenesis of AD was initially suggested by Alois

Alzheimer himself in 1910). In fact, AD plaques are formed by Ap deposits, degenerating neurites, astroglial processes and activated microglial cells.

The specific role of astrocytes in the pathogenesis of AD began to be considered after it was discovered that astrocytes are natural scavengers of Ap, and its particularly toxic truncated form Ap42 (Ap42 is a fragment of Ap, which contains 42 amino acids and is the product of cleavage of amyloid precursor protein by beta- and gamma secretases). Astrocytes can detect and extend their processes towards deposits of Ap, and then astrocytes are able to take up and degrade the Ap. One of the possible (and recently discussed) scenarios of AD progression may be the following (Figure 10.7). At the very early stages of AD, neurones start to overproduce Ap, which compromises their dendrites and leads to their degeneration and release of Ap and other neuronal products; these activate astrocytes whose domains embrace the compromised neurone. Astrocytes begin to clear the neuronal debris and accumulate the Ap. Remarkably, AD results in a selective increase of the neuronal type of nicotinic acetylcholine receptor (so-called a7nACHRs) in astroglial cells; incidentally, Ap42 has a very high affinity for a7nACHRs, which probably explains the high vulnerability of cholin-ergic neurones to AD. It may well be that Ap42 is accumulated by astrocytes together with a7nACHRs. Astrocytes eventually become overloaded with Ap, which affects their function and results in decreased support of other neuronal processes within the astrocyte domain. This may initiate degeneration of the next neurone and trigger distant accumulation of Ap. Importantly, astrocytes may even be instrumental in providing the route for Ap neurotoxicity: in vitro experiments have shown that treatment of astroglial-neuronal co-cultures with Ap results in the appearance of [Ca2+]j oscillations in astrocytes, without any apparent [Ca2+]j changes in neurones. Nonetheless, these astroglial oscillations led to neuronal death in ~24 hours; inhibition of glial [Ca2+]j responses was neuroprotective. When the whole domain is thus degenerated, it undergoes lysis and the initial plaque is formed. Then, neighbouring astrocytes detect the extracellular Ap deposit, become activated and send their processes towards the plaque, trying to clear the excess of Ap. The repetition of this process eventually recruits increasing numbers of astrocytes and through them astrocytic domains with their neurones, which in turn leads to dissemination of the plaques. The latter in fact are polymorphic and may be formed either by lysis of neurones and astrocytes or by local death of astroglial cells only. The pathogenesis of AD also affects oligodendrocytes, whereby AD is associated with significant loss of myelin, which affects tracts connecting cortical areas.

The process of cell death and plaque formation triggers activation of microglia, which occurs both locally in the vicinity of the plaques and diffusely throughout the brain parenchyma. Activated microglia surround the plaques and participate in their formation. The actual role of microglia in AD progression remains unclear, as they may have both protective and deleterious effects. The initial suggestion that activated microglia may accumulate and remove Ap fibrils, although observed in vitro in microglial cultures treated with Ap, has not been confirmed in vivo.

Stages Alzheimer Disease

Figure 10.7 Possible role of astrocytes in the pathogenesis of Alzheimer's disease. In the first stage of the disease astrocytes detect ^-amyloid, released by affected neurones, and withdraw their processes from both affected and neighbouring, intact, neurones. This leads to the second stage, when neurites lacking astroglial support begin to degenerate; the astrocyte by itself starts to accumulate ^-amyloid. In the third stage neurones and astrocytes die and their debris attracts activated microglial cells and induces reactive astrogliosis. Reactive astrocytes, activated microglial cells and ^-amyloid released from dead cells form the plaque. (Modified from Nagele RG, Wegiel J, Venkataraman V, Imaki H, Wang KC (2004) Contribution of glial cells to the development of amyloid plaques in Alzheimer's disease. Neurobiol Aging 25, 663-74)

Figure 10.7 Possible role of astrocytes in the pathogenesis of Alzheimer's disease. In the first stage of the disease astrocytes detect ^-amyloid, released by affected neurones, and withdraw their processes from both affected and neighbouring, intact, neurones. This leads to the second stage, when neurites lacking astroglial support begin to degenerate; the astrocyte by itself starts to accumulate ^-amyloid. In the third stage neurones and astrocytes die and their debris attracts activated microglial cells and induces reactive astrogliosis. Reactive astrocytes, activated microglial cells and ^-amyloid released from dead cells form the plaque. (Modified from Nagele RG, Wegiel J, Venkataraman V, Imaki H, Wang KC (2004) Contribution of glial cells to the development of amyloid plaques in Alzheimer's disease. Neurobiol Aging 25, 663-74)

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