"It would appear that pathways of impaired autophagy are inherently conducive to co-localization of
neurofilaments, with the formation of neurofibrillary tangles and with synapse loss. Indeed, intracytoplasmic
amyloidogenesis might, in specific ways, be a component system in production of both synapse loss and
neuronal cell death largely in terms of the etiologic cause of the amyloidogenesis as a prototype of cellular
degeneration in its own right. It might perhaps be relevant to consider how synapse loss and neuronal cell
death would implicate reactivity of lysosomes that affects the metabolic activity of neurons. A low neuronal
metabolic rate would inherently affect trafficking systems and also the production of a variable response to
different insults ranging from neurotrophin factor lack to ischemia primarily evolving as phenomena centered
on cerebral cortical neurons. Impaired autophagy implicating abnormal lysosomal activation would promote the
accumulation of ubiquinated endproducts of neuronal metabolism with the appearance of phosphorylated
neurofilament aggregates and granulovacuolar degeneration. Interpretative assessment of neuronal inclusion
body phenomena in selected neuronal subsets might implicate a failed central pathway mechanism promoting
the development of neurodegeneration. Indeed, it is in terms of primary lysosomal disease that major
neuropathologic lesions in Alzheimer`s disease would be conducive to subsequent slowly progressive
neurodegeneration as a selective neuronal subset phenomenon. It might be significant to recognize
amyloidogenesis as a reflected consequence of such lysosomal involvement beyond simple considerations of
directly involved proapoptosis or cell cyclical activity but within a strict context of impaired turnover events
affecting cell organelles in particular."