Senile plaques, or neuritic plaques, are spherical bodies that typically contain a central core of amyloid surrounded by degenerating neuronal processes.
The amyloid plaque is a heterogeneous class of protein aggregates with β-pleated structure. In a general sense, these are called senile plaques (SP) (reviewed by Dickson 1997 ). SPs are varyingly composed of compact or non-compact amyloid, and can be associated with degeneration of nearby neuronal cell processes (neurites) that may be dystrophic or PHF-type neurites (reviewed by Dickson 1997 ). Paired helical filaments (PHFs) will be discussed more fully in a following section.
The “classical” senile plaque (SP) is a neuritic plaque of a few microns in diameter that consists of a dense central core of radiating amyloid fibrils surrounded by a rim of dystrophic PHF-type neurites together with reactive microglia and sometimes astrocytes (reviewed by Dickson 1997 ). The majority of amyloid plaques are diffuse and these may spread over hundreds of microns and they comprise a considerable proportion of SP. Although they consist of amyloid and may contain PHF-type neurites, the amyloid is less compact and the associated microglial reactions are weaker and rarer (Yamaguchi et al 1988 ). Amyloid deposits are detected histochemically using the dye Congo red.
Amyloid deposition is frequent in aging, even in cognitively intact individuals: however these deposits are non-compact or diffuse, lack PHF-type neurites and display only minimal glial reaction (reviewed by Dickson 1997 ).
Amyloid deposits are composed of straight, unbranching fibrils of 6-10nm at the ultrastructural level. Seminal work by Glenner and Wong identified these deposits to be composed mostly of the aggregated 4 kDa β-amyloid (Aβ) protein (Glenner and Wong 1984 ). Aβ is heterogeneous in size, but the predominant species found in amyloid plaques is Aβ42 (Iwatsubo et al 1994 ). Control subjects with high plasma Aβ42 levels have an increased chance of developing AD (Mayeux et al 1999 ). Aggregation of Aβ to form insoluble deposits requires time and may occur by a nucleation type process. It is possible that the formation of plaques requires additional factors. In addition to Aβ, amyloid plaques are associated with a variety of brain and serum-derived proteins, such as complement proteins (Head et al 2001 ), apolipoproteins and protease inhibitors (reviewed by Dickson 1997). Activation of the complement pathway may attract and activate microglial cells (Head et al 2001), and brain inflammation is a key feature in the development of AD. It is likely that the presence of other factors is in response to Aβ, but the temporal sequence of events is unclear.
The majority of Aβ plaques are found in the grey matter of the brain (reviewed by Braak and Del Tredici 2004 ). Within the brain, progression of amyloid pathology generally proceeds in a particular manner, and depending on the brain regions affected this can be classified into stages referred to as Braak stages (A-C).
The predilection site for the deposition of amyloid is the cerebral cortex, in particular the isocortex. At Stage A, low densities of amyloid deposits are found in the isocortex, particularly in the basal portions of the frontal, temporal and occipital lobe. Furthermore, some amyloid is found in the presubiculum and Pre-β and Pre-γ layers of the entorhinal complex. Stage B shows an increase in amyloid deposits in almost all isocortical association areas and only the primary sensory areas and primary motor field remain almost devoid of deposits. There is a mild involvement of the hippocampal formation and amyloid may be found in the entorhinal cortex. Stage C is mainly characterised by the fact that virtually all isocortical areas are affected, while deposits in the hippocampal formation show the same pattern as Stage B.
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